Methods and systems for crystallizing and isolating individual cannabinoids

ABSTRACT

The present disclosure provides methods for selectively crystallizing cannabinoids from solutions containing a plurality of cannabinoids. The present disclosure further provides methods for separating a crystallized cannabinoid from a mixture of cannabinoids.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.17/494,898, filed Oct. 6, 2021, which claims the benefit of priority toU.S. Provisional Application No. 63/172,244, filed on Apr. 8, 2021. Thecontents of the aforementioned patent documents are incorporated byreference herein in their entirety.

FIELD

The present disclosure generally relates to methods of selectivelycrystallizing and purifying cannabinoids from a mixture of cannabinoids.

BACKGROUND

Cannabis has over 80 active constituents with potential therapeuticbenefits. For instance, research shows that cannabinoids isolated fromCannabis stabilize blood sugar, provide relief from chronic pain, helpwith weight loss, improve depression and anxiety, prevent seizures, andallow broken bones to heal more quickly.

The most common extraction methods used to isolate cannabinoids usesolvents such as ethanol, hexane, butane, pentane, or propane. Thesemethods require tightly regulated environments, because theaforementioned solvents are flammable. Furthermore, these methods resultin chemical impurities in the extracted cannabinoid compositions, whichcan produce undesirable color, tastes/smells, and may even be dangerousfor human consumption.

There is a need in the art for safer methods of extracting and purifyingcannabinoids from Cannabis.

SUMMARY

There is an unmet need for improved methods for extraction andpurification of cannabinoids. The present disclosure provides methods ofextracting and purifying cannabinoids from Cannabis that do not usetraditional solvents or require expensive processing equipment. Themethods provided herein do not require ethanol winterization, pentane orhexane solvation and crystallization, or ether washes. Nor do themethods require expensive explosive proof equipment or solvent reactors.The methods described herein result in pure cannabinoid compositions. Insome embodiments, the pure cannabinoid products are organic, because themethods of producing them do not utilize non-organic solvents.Additionally, the methods for extraction and purification ofcannabinoids described herein are zero waste processes, because thebyproducts are used in further refining processes.

Provided herein is a method of selectively crystallizing a selectedcannabinoid from a solution of cannabinoids, comprising: (a) providing asolution containing a plurality of cannabinoids, wherein the selectedcannabinoid is present in the solution at a concentration greater thanor equal to its supersaturation point at −5° C., and wherein theselected cannabinoid is the highest concentration cannabinoid in thesolution, and wherein said solution is substantially free of anyexogenous solvent; (b) increasing the temperature of the solution untilthe selected cannabinoid is substantially dissolved in the solution; and(c) decreasing the temperature of the solution to about −5° C. or lowerto produce a cooled solution wherein the selected cannabinoidcrystallizes out of solution, thereby forming crystals of the selectedcannabinoid. In some embodiments, the solution is a primary cannabisextract. In some embodiments, step (b) comprises increasing thetemperature to between about 50° C. and about 79° C. In someembodiments, step (c) comprises decreasing the temperature to betweenabout −5° C. and about −20° C. In some embodiments, the cooled solutionis exposed to a nucleation factor, wherein the nucleation factor isselected from the group consisting of introducing a crystal of theselected cannabinoid into the cooled solution, introducing the cooledsolution to a vacuum or a vacuum oven, mechanically agitating the cooledsolution, increasing or maintaining the moisture content of the cooledsolution, and aerating the cooled solution. In some embodiments, theselected cannabinoid is selected from the group consisting ofcannabidiol (CBD), tetrahydrocannabinol (THC), tetrahydrocannabivarin(THCV), cannabidiolic acid (CBDA), cannabidivarin (CBDV),tetrahydrocannabinolic acid (THCA), cannabigerol (CBG), cannabinol(CBN), cannabinolic acid (CBNA), cannabidivarinic acid (CBDVA),cannabigerolic acid (CBGA), cannabichromenic acid (CBCA), andcannabichromene (CBC). In some embodiments, the solution of cannabinoidsis a Cannabis oil that is substantially free of cutting agents. In someembodiments, the solution of cannabinoids comprises less than 1%, 0.9%,0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% exogenous solvents. Insome embodiments, 95% of the selected cannabinoid is crystallized out ofthe cooled solution. In some embodiments, the selected cannabinoidcrystallizes out of solution within about 10 hours. In some embodiments,a vacuum is applied to the cooled solution. In some embodiments, thecrystals of the selected cannabinoid comprise crystals that are greaterthan about 25 μm in size.

In some embodiments, provided herein is a method of purifying a selectedcannabinoid from a mixture of cannabinoids, said method comprising: (a)providing a mixture of cannabinoids comprising a crystallizedcannabinoid, wherein the crystallized cannabinoid comprises crystalsthat are at least about 25 μm in size; (b) forcing the mixture ofcannabinoids through a filter, said filter having a pore size smallerthan about 25 μm; wherein this step is performed at a temperature belowthe melting point of the crystallized cannabinoid, wherein thecrystallized cannabinoid remains on the filter; and (c) collecting thecrystallized cannabinoid from the filter, thereby purifying the selectedcannabinoid. In some embodiments, step (b) is performed between about0.5° C. and 10° C. below the melting point of the crystallizedcannabinoid. In some embodiments, the selected cannabinoid is selectedfrom the group consisting of consisting of cannabidiol (CBD),tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV), cannabidiolicacid (CBDA), cannabidivarin (CBDV), tetrahydrocannabinolic acid (THCA),cannabigerol (CBG), cannabigerolic acid (CBGA), cannabinol (CBN),cannabinolic acid (CBNA), cannabidivarinic acid (CBDVA),cannabichromenic acid (CBCA), and cannabichromene (CBC). In someembodiments, the mixture of cannabinoids is forced through the filtervia centrifugation, application of pressure, or application of a vacuum.In some embodiments, the crystallized cannabinoid is washed with asolvent at a temperature between about 1° C. and 8° C. In someembodiments, the collected crystallized cannabinoid is at least 98%pure.

In some embodiments, provided herein is a method of purifying a selectedcannabinoid from a solution containing a plurality of cannabinoids,comprising: (a) selectively crystallizing the selected cannabinoid fromthe solution by: (i) increasing the temperature of the solution untilthe selected cannabinoid is substantially dissolved in the solution,wherein the selected cannabinoid is present in the solution at aconcentration greater than or equal to its supersaturation point; andwherein the selected cannabinoid is the highest concentrationcannabinoid in the solution; (ii) decreasing the temperature of thesolution to about −5° C. or lower to produce a cooled solution wherein95% of the selected cannabinoid has crystallized out of solution intocannabinoid crystals; and (b) separating the selected cannabinoidcrystals from the cooled solution. In some embodiments, the cannabinoidis separated from the cooled solution by: (i) forcing the cooledsolution through a filter, said filter having a pore size smaller thanabout 2 μm or smaller than about 25 μm; wherein this step is performedat a temperature below the melting point of the crystallizedcannabinoid; and (ii) collecting the crystallized cannabinoid from thefilter, thereby separating the selected cannabinoid from the cooledsolution. In some embodiments, the mixture of cannabinoids is forcedthrough the filter via centrifugation, application of pressure, orapplication of a vacuum. In some embodiments, the temperature of thesolution is increased in step (a)(i) to between about 50° C. and about79° C. In some embodiments, the temperature of the solution is decreasedin step (a)(ii) to below about −5° C. In some embodiments, the methodcomprises exposing the cooled solution to a nucleation factor, whereinthe nucleation factor is selected from the group consisting ofintroducing a crystal of the selected cannabinoid into the cooledsolution, introducing the cooled solution to a vacuum or a vacuum oven,mechanically agitating the cooled solution, increasing or maintainingthe selected cannabinoid is selected from the group consisting ofcannabidiol (CBD), tetrahydrocannabinol (THC), tetrahydrocannabivarin(THCV), cannabidiolic acid (CBDA), cannabidivarin (CBDV),tetrahydrocannabinolic acid (THCA), cannabigerol (CBG), cannabigerolicacid (CBGA), cannabinol (CBN), cannabinolic acid (CBNA),cannabidivarinic acid (CBDVA), cannabichromenic acid (CBCA), andcannabichromene (CBC). In some embodiments, the solution of cannabinoidsis a Cannabis oil that does not contain any cutting agents. In someembodiments, the solution of cannabinoids comprises less than 1%, 0.9%,0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% exogenous solvents. Insome embodiments, 95% of the selected cannabinoid is crystallized out ofthe cooled solution. In some embodiments, the selected cannabinoidcrystallizes out of solution within about 10 hours. In some embodiments,the method comprises applying a vacuum to the cooled solution. In someembodiments, the crystals of the selected cannabinoid comprise crystalsthat are at least about 25 μm in size.

Provided herein is a method for purifying a selected cannabinoid from asolution containing a plurality of cannabinoids, comprising: (a)selectively crystallizing the selected cannabinoid from the solution by:(i) increasing the temperature of the solution until the selectedcannabinoid is substantially dissolved in the solution, wherein theselected cannabinoid is present in the solution at a concentrationgreater than or equal to its supersaturation point; and wherein theselected cannabinoid is the highest concentration cannabinoid in thesolution; (ii) decreasing the temperature of the solution to about −5°C. or lower to produce a cooled solution wherein 95% of the selectedcannabinoid has crystallized out of solution into cannabinoid crystals;(b) separating the selected cannabinoid crystals from the cooledsolution by forcing the cooled solution through a filter viacentrifugation, said filter having a pore size smaller than about 2 μm;wherein this step is performed at a temperature below the melting pointof the crystallized cannabinoid; and (c) collecting the crystallizedcannabinoid from the filter, thereby separating the selected cannabinoidfrom the cooled solution. In some embodiments, the method comprisesexposing the cooled solution to a nucleation factor, wherein thenucleation factor is selected from the group consisting of introducing acrystal of the selected cannabinoid into the cooled solution,introducing the cooled solution to a vacuum or a vacuum oven,mechanically agitating the cooled solution, increasing or maintainingthe moisture content of the cooled solution, and aerating the cooledsolution. In some embodiments, the nucleation factor comprisesmechanically agitating the cooled solution, introducing the cooledsolution to a vacuum or a vacuum oven, or combinations thereof. In someembodiments, the nucleation factor comprises mechanically agitating thecooled solution, introducing a crystal of the selected cannabinoid intothe cooled solution, and introducing the cooled solution to a vacuum ora vacuum oven, or combinations thereof.

Provided herein is a method of purifying a selected cannabinoid from asolution containing a plurality of cannabinoids, comprising: (a)selectively crystallizing the selected cannabinoid from the solution by:(i) increasing the temperature of the solution until the selectedcannabinoid is substantially dissolved in the solution; (ii) decreasingthe temperature of the solution to about −5° C. or lower to produce acooled solution wherein 95% of the selected cannabinoid has crystallizedout of solution into cannabinoid crystals; (b) separating the selectedcannabinoid crystals from the cooled solution by forcing the cooledsolution through a filter via centrifugation, said filter having a poresize smaller than about 2 μm; wherein this step is performed at atemperature below the melting point of the crystallized cannabinoid; and(c) collecting the crystallized cannabinoid from the filter, therebyseparating the selected cannabinoid from the cooled solution. In someembodiments, the method comprises exposing the cooled solution to anucleation factor, wherein the nucleation factor is selected from thegroup consisting of introducing a crystal of the selected cannabinoidinto the cooled solution, introducing the cooled solution to a vacuum ora vacuum oven, mechanically agitating the cooled solution, increasing ormaintaining the moisture content of the cooled solution, and aeratingthe cooled solution. In some embodiments, the nucleation factorcomprises mechanically agitating the cooled solution, introducing thecooled solution to a vacuum or a vacuum oven, or combinations thereof.In some embodiments, the nucleation factor comprises mechanicallyagitating the cooled solution, introducing a crystal of the selectedcannabinoid into the cooled solution, and introducing the cooledsolution to a vacuum or a vacuum oven, or combinations thereof. In someembodiments, the selected cannabinoid is present in the solutioncontaining a plurality of cannabinoids at a concentration of greaterthan 10% by weight of the solution.

Provided herein is a method of crystallizing a selected cannabinoid froma cannabinoid solution, comprising: (a) providing a cannabinoid solutioncontaining a substantially dissolved selected cannabinoid, wherein theselected cannabinoid is present in the solution at a concentrationgreater than or equal to its supersaturation point, and wherein theselected cannabinoid is the highest concentration cannabinoid in thesolution; and (b) exposing the cannabinoid solution of step (a) tonucleation factors comprising mechanical agitation and a vacuum for atime period sufficient to crystallize the selected cannabinoid. In someembodiments, the solution of (a) is produced by increasing thetemperature of a cannabinoid solution until the selected cannabinoid issubstantially dissolved in the solution. In some embodiments, thesolution of (a) is produced by increasing the temperature of acannabinoid solution until the selected cannabinoid is substantiallydissolved in the solution, wherein the temperature is increased to fromabout 50° C. and about 79° C. In some embodiments, the supersaturationpoint is greater than or equal to 30% by weight of the solution. In someembodiments, the cannabinoid solution is substantially free of anyalcohol. In some embodiments, the cannabinoid solution comprises lessthan 15%, less than 10%, or less than 5% alcohol by weight of thesolution. In some embodiments, the cannabinoid solution is substantiallyfree of any exogenous solvent. In some embodiments, the cannabinoidsolution comprises less than 15%, less than 10%, or less than 5%exogenous solvent by weight of the solution. In some embodiments, themethod comprises exposing the dissolved cannabinoid solution to anadditional nucleation factor, wherein the nucleation factor is selectedfrom the group consisting of: cold shock, introducing a crystal of theselected cannabinoid into the dissolved cannabinoid solution, aeratingthe solution, and combinations thereof. In some embodiments, the methodcomprises mechanically agitating the dissolved cannabinoid solutionbefore exposing the cannabinoid solution to the vacuum, while thecannabinoid solution is exposed to the vacuum, or a combination thereof.In some embodiments, the selected cannabinoid is selected from the groupconsisting of cannabidiol (CBD), tetrahydrocannabinol (THC),tetrahydrocannabivarin (THCV), cannabidiolic acid (CBDA), cannabidivarin(CBDV), tetrahydrocannabinolic acid (THCA), cannabigerol (CBG),cannabinol (CBN), cannabinolic acid (CBNA), cannabidivarinic acid(CBDVA), cannabigerolic acid (CBGA), cannabichromenic acid (CBCA), andcannabichromene (CBC). In some embodiments, the selected cannabinoid isCBD. In some embodiments, the vacuum is stronger than about −5 inHg. Insome embodiments, the method provides crystallization of at least 70% ofthe selected cannabinoid by weight of the solution within 48 hours.

Provided herein is a method of purifying a selected cannabinoid from asolution of cannabinoids, said method comprising: (a) crystallizing theselected cannabinoid from the solution by: (i) providing a cannabinoidsolution containing a substantially dissolved selected cannabinoid,wherein the selected cannabinoid is present in the solution at aconcentration greater than or equal to its supersaturation point, andwherein the selected cannabinoid is the highest concentrationcannabinoid in the solution; (ii) exposing the cannabinoid solution ofstep (a)(i) to a nucleation factor for a time period sufficient tocrystallize the selected cannabinoid, wherein the nucleation factor ismechanical agitation and vacuum, thereby producing cannabinoid crystals;and (b) separating the selected cannabinoid crystals from thecannabinoid solution of step (a)(ii). In some embodiments, thecannabinoid solution is substantially free of any alcohol. In someembodiments, the cannabinoid solution comprises less than 15%, less than10%, or less than 5% alcohol by weight of the solution. In someembodiments, the cannabinoid solution is substantially free of anyexogenous solvent. In some embodiments, the cannabinoid solutioncomprises less than 15%, less than 10%, or less than 5% exogenoussolvent by weight of the solution. In some embodiments, step (b)comprises (i) forcing the cannabinoid solution and cannabinoid crystalsthrough a filter; wherein this step is performed at a temperature belowthe melting point of the cannabinoid crystals; and (ii) collecting thecannabinoid crystals from the filter, thereby separating the selectedcannabinoid from the cannabinoid solution. In some embodiments, step (b)comprises (i) forcing the cannabinoid solution and cannabinoid crystalsthrough a filter via centrifugation, application of pressure, orapplication of a vacuum; wherein this step is performed at a temperaturebelow the melting point of the cannabinoid crystals; and (ii) collectingthe cannabinoid crystals from the filter, thereby separating theselected cannabinoid from the cannabinoid solution. In some embodiments,step (b) comprises (i) forcing the cannabinoid solution and cannabinoidcrystals through a filter via centrifugation; wherein this step isperformed at a temperature below the melting point of the cannabinoidcrystals; and (ii) collecting the cannabinoid crystals from the filter,thereby separating the selected cannabinoid from the cannabinoidsolution. In some embodiments, the solution of (a) is produced byincreasing the temperature of the cannabinoid solution until theselected cannabinoid is substantially dissolved in the solution. In someembodiments, the temperature is increased to between about 50° C. andabout 79° C. In some embodiments, the supersaturation point is greaterthan or equal to 30% by weight of the solution. In some embodiments, themethod comprises exposing the dissolved cannabinoid solution to anadditional nucleation factor, wherein the nucleation factor is selectedfrom the group consisting of: cold shock, introducing a crystal of theselected cannabinoid into the dissolved cannabinoid solution, aeratingthe solution, and combinations thereof. In some embodiments, the methodcomprises mechanically agitating the dissolved cannabinoid solutionbefore exposing the cannabinoid solution to the vacuum, while thecannabinoid solution is exposed to the vacuum, or a combination thereof.In some embodiments, the selected cannabinoid is selected from the groupconsisting of cannabidiol (CBD), tetrahydrocannabinol (THC),tetrahydrocannabivarin (THCV), cannabidiolic acid (CBDA), cannabidivarin(CBDV), tetrahydrocannabinolic acid (THCA), cannabigerol (CBG),cannabinol (CBN), cannabinolic acid (CBNA), cannabidivarinic acid(CBDVA), cannabigerolic acid (CBGA), cannabichromenic acid (CBCA), andcannabichromene (CBC). In some embodiments, the selected cannabinoid isCBD. In some embodiments, the vacuum is stronger than about −5 inHg. Insome embodiments, the method provides crystallization of at least 70% ofthe selected cannabinoid by weight of the solution within 48 hours.

In some embodiments, provided herein is a method of purifying a selectedcannabinoid from a cannabinoid solution, said method comprising: (a)crystallizing the selected cannabinoid from the solution by: (i)providing a cannabinoid solution containing a substantially dissolvedselected cannabinoid, wherein the selected cannabinoid is present in thesolution at a concentration greater than or equal to its supersaturationpoint; (ii) exposing the cannabinoid solution of step (a)(i) to anucleation factor for a time period sufficient to crystallize theselected cannabinoid, wherein the nucleation factor is mechanicalagitation and vacuum, thereby producing cannabinoid crystals; and (b)separating the selected cannabinoid crystals from the cannabinoidsolution of step (a)(ii) by: (i) forcing the cannabinoid solutionthrough a filter; wherein this step is performed at a temperature belowthe melting point of the cannabinoid crystals; and (ii) collecting thecannabinoid crystals from the filter, thereby separating the selectedcannabinoid from the cannabinoid solution. In some embodiments, themethod provides crystallization of at least 70% of the selectedcannabinoid by weight of the solution within 48 hours.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows CBD crystals resulting from the method of selectivecrystallization of cannabinoids described herein.

FIG. 2 is an image of THC-rich starting material for crystallization.

FIG. 3A is an image of THC crystals beginning to form after the THC-richsolution is cooled.

FIG. 3B is an image of THC crystals resulting from the method ofselective crystallization of cannabinoids described herein.

FIG. 4A is an image of a THC powder produced by (i) crystallizing THCfrom a solution containing a plurality of cannabinoids; (ii) separatingthe THC crystals from the solution by applying them to a filter; (iii)washing the THC crystals in cold water; and (iv) drying the THC crystalsin a vacuum oven.

FIG. 4B is another image of a THC powder produced by (i) crystallizingTHC from a solution containing a plurality of cannabinoids; (ii)separating the THC crystals from the solution by applying them to afilter; (iii) washing the THC crystals in cold water; and (iv) dryingthe THC crystals in a vacuum oven.

FIG. 5 is an image of CBD crystals that are 99.5% pure.

FIG. 6 is an image of THC crystals that are 100% pure.

FIGS. 7A-7J are images of a solution containing a plurality ofcannabinoids before or 24 hours after optional exposure to a nucleationfactor, wherein the selected cannabinoid is CBD. FIG. 7A is an image ofa solution containing a plurality of cannabinoids 24 hours aftertemperature modulation. No nucleation factor is added to the solution ofFIG. 7A. FIG. 7B is an image of a solution containing a plurality ofcannabinoids 24 hours after exposure to a vacuum oven and cold-shocked(after 24 hours). FIG. 7C is an image of a solution containing aplurality of cannabinoids 24 hours after the solution is mechanicallyagitated and cold-shocked. FIG. 7D is an image of a solution containinga plurality of cannabinoids 24 hours after a seed crystal is introducedto a solution that has been cold-shocked. FIG. 7E is an image of asolution containing a plurality of cannabinoids before a seed crystal isintroduced to a solution and after the solution has been cold-shocked.FIG. 7F is an image of a solution containing a plurality of cannabinoids24 hours after a seed crystal is introduced to the solution and thesolution is mechanically agitated. FIG. 7G is an image of a solutioncontaining a plurality of cannabinoids 24 hours after the solution ismechanically agitated and exposed to a vacuum oven. FIG. 7H is an imageof a solution containing a plurality of cannabinoids 24 hours after aseed crystal is introduced to the solution and the solution ismechanically agitated, cold-shocked, and exposed to a vacuum oven. FIG.7I is an image of a solution containing a plurality of cannabinoids 24hours after a seed crystal is introduced to the solution and thesolution is exposed to a vacuum oven. FIG. 7J shows images of the CBDcrystals of the samples of FIG. 7I, FIG. 7H, FIG. 7G, and FIG. 7B (leftto right).

FIGS. 8A-8D are images of a CBD solution containing a plurality ofcannabinoids that has heated to 60° C., mixed until the CBD wasdissolved, cooled to −20° C., and exposed to a vacuum oven at pressuresof −5 inHg (FIG. 8A), −10 inHg (FIG. 8B), −15 inHg (FIG. 8C), or −20inHg (FIG. 8D). Images are collected one hour after exposure to thevacuum oven.

FIG. 9A is an image of a CBD crystal washed in the presence of a rotorstator homogenizer.

FIG. 9B is an image of a CBD crystal washed in the absence of a rotorstator homogenizer.

FIG. 10A is an image of a CBD crystal that is separated from a solutioncontaining a plurality of cannabinoids using centrifugation. FIG. 10B isan image of a CBD crystal that is separated from a solution containing aplurality of cannabinoids using vacuum filtration.

FIG. 11A is an image of a solution containing a plurality ofcannabinoids 24 hours after the solution is heated to 60° C. for fiveminutes and allowed to cool to room temperature. FIG. 11B is an image ofCBD crystals formed from a solution containing a plurality ofcannabinoids 24 hours after the solution has been heated to 60° C.,mixed until the CBD was dissolved, and cooled to −20° C. The cooledsolution has been mechanically agitated and exposed to a vacuum oven anda CBD seed crystal. FIG. 11C is a micrograph that shows the size of theCBD crystals of FIG. 11B.

FIG. 11D is a micrograph that shows the size of the CBD crystals of FIG.11A.

FIGS. 12A-D show CBD crystallization from a solution containing CBD asthe only cannabinoid in the solution at concentrations of 60% CBD (FIG.12A), 50% CBD (FIG. 12B), 40% CBD (FIG. 12C), and 30% CBD (FIG. 12D).After each solution of FIGS. 12A-D was heated to 60° C., the solutionswere exposed to the following nucleation factors: agitation (intensestirring), cold shock (cooling solution to −20° C. and mixing),introduction of a CBD seed crystal, and exposure to a vacuum at apressure of −25 inHg.

FIGS. 13A-D show THCA crystallization from a solution containing THCA asthe only cannabinoid in the solution at concentrations of 60% THCA (FIG.13A), 50% THCA (FIG. 13B), 40% THCA (FIG. 13C), and 30% THCA (FIG. 13D).After each solution of FIGS. 13A-D was heated to 60° C., the solutionswere exposed to the following nucleation factors: agitation (intensestirring), cold shock (cooling solution to −20° C. and mixing),introduction of a THCA seed crystal, and exposure to a vacuum at apressure of −25 inHg.

FIGS. 14A-F show crystallization of CBD from a CBD-rich solutioncontaining a plurality of cannabinoids. After each solution of FIGS.14A-D was heated to 60° C., the solutions were exposed to the followingnucleation factors: agitation (intense stirring), cold shock (coolingsolution to −20° C. and mixing), introduction of a CBD seed crystal, andexposure to a vacuum at a pressure of −25 inHg. FIG. 14A showscrystallization of CBD when CBD is present in the solution at aconcentration of 31.3% w/w. The cloudy layer on top is CBD crystals. Thebottom layer is MCT coconut oil. At the interface of the coconut oil andcrystals, crystals appear to proceed into the MCT coconut oil layer.FIG. 14B shows crystallization of CBD when CBD is present in thesolution at a concentration of 19.6% w/w. FIG. 14C shows crystallizationof CBD when CBD is present in the solution at a concentration of 15.7%w/w. FIG. 14D shows crystallization of CBD when CBD is present in thesolution at a concentration of 11.7% w/w. FIG. 14E shows crystallizationof CBD when CBD is present in the solution at a concentration of 7.8%w/w. FIG. 14F shows crystallization of CBD when CBD is present in thesolution at a concentration of 3.9% w/w.

FIGS. 15A-J show cannabinoid samples allowed to crystallize naturally.Samples 9 (FIG. 15A), 4 (FIG. 15B), 1 (FIG. 15C), and 8 (FIG. 15D) onlycrystallized after 95 days. Samples 2 (FIG. 15E), 5 (FIG. 15F), 3 (FIG.15G), 6 (FIG. 15H), 7 (FIG. 15I), and 10 (FIG. 15J) did not crystallizeat all during the period of observation (95 days).

FIG. 16 shows crystallization of CBD from a solution containing 24% CBD,1% THCA, and 75% oleic acid.

FIG. 17A shows the effect of introducing a vacuum nucleation factor to acannabinoid solution. The microbubbles in the image are uniform and haveexpanded as a result of exposure to the vacuum.

FIG. 17B shows the effect of agitating and applying cold shock to acannabinoid solution. These nucleation factors thicken the cannabinoidsolution and result in bubble formation which aids cannabinoidnucleation.

DETAILED DESCRIPTION I. Definitions

The term “a” or “an” refers to one or more of that entity, i.e., canrefer to a plural referent. As such, the terms “a” or “an”, “one ormore” and “at least one” are used interchangeably herein. In addition,reference to “an element” by the indefinite article “a” or “an” does notexclude the possibility that more than one of the elements is present,unless the context clearly requires that there is one and only one ofthe elements.

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases. Multiple elements listed with“and/or” should be construed in the same fashion, i.e., “one or more” ofthe elements so conjoined. Other elements may optionally be presentother than the elements specifically identified by the “and/or” clause,whether related or unrelated to those elements specifically identified.Thus, as a non-limiting example, a reference to “A and/or B”, when usedin conjunction with open-ended language such as “comprising” can refer,in one embodiment, to A only (optionally including elements other thanB); in another embodiment, to B only (optionally including elementsother than A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

Throughout this application, the term “about” is used to indicate that avalue includes the inherent variation that exists among the samplesbeing measured. Unless otherwise stated or otherwise evident from thecontext, the term “about” means within 10% above or below the reportednumerical value (except where such number would exceed 100% of apossible value or go below 0%). When used in conjunction with a range orseries of values, the term “about” applies to the endpoints of the rangeor each of the values enumerated in the series, unless otherwiseindicated. As used in this application, the terms “about” and“approximately” are used as equivalents.

Herein, the terms “comprise”, or variations such as “comprises” or“comprising”, will be understood to imply the inclusion of a statedelement or integer or group of elements or integers but not theexclusion of any other element or integer or group of elements orintegers.

As used within the context of this application, the term “purified”means extracted, isolated, and/or separated from other compounds,formulations, compositions, matter, and/or mass. In some embodiments, acannabinoid may be separated from other cannabinoids, terpenes, waxes,and fats.

The term “reference value” or “control value” refers to a value ormeasurement obtained from an experimental control group or to a baselinevalue (e.g., purity) obtained from a solution containing a plurality ofcannabinoids prior to performance of the methods of the disclosure.

The term “substantially pure” refers to a cannabinoid having achromatographic purity of greater than about 95% by weight, greater thanabout 96% by weight, greater than about 97% by weight, greater thanabout 98% by weight, or greater than about 99% by weight.

The term “Cannabis plant part” refers to any part of a Cannabis plantincluding but not limited to the embryo, shoot, root, stem, seed,stipule, leaf, petal, flower, inflorescence, bud, ovule, bract,trichome, branch, petiole, internode, bark, pubescence, tiller, rhizome,frond, blade, pollen, stamen, mesocarp, epicarp, endosperm, spermoderm,and disk.

The term “cannabinoid composition” refers to a composition comprising atleast one cannabinoid, for example, at least one, two, three, four,five, six, seven, eight, nine, ten, 11, 12, 13, 14, 15, 16, 17, 18, 19,or 20 cannabinoids.

Various concentration expressions, including volume concentrations,weight concentrations, and mass concentrations, are utilized to describethe percentage of a component in a solution. Volume concentration hasunits of % v/v, where v/v is volume per volume. If a solution contains5% v/v of a component, 5 mL of the component is in a total solution of100 mL, for example. Weight concentration of a solution is expressed as% w/w, where w/w is weight per weight. If a solution contains 30% w/w ofsodium chloride, an example solution contains 30 g of sodium chlorideand 70 g of other components of the solution, such as the solvent. Massconcentration of a solution is expressed as % w/v, where w/v is weightper volume. If 1 g of sodium chloride is dissolved in a solution with atotal volume of 100 mL, a 1% w/v sodium chloride solution has been made.

As used herein, the term “exogenous solvent” refers to any solvent thatis not derived from the Cannabis plant. Exogeneous solvents include, butare not limited to, ethanol, iso-propanol, hexane, methyl ethyl ketone,acetone, ethyl ether, butane, propane, and liquid CO2.

The term “selectively” as it refers to crystallizing a selectedcannabinoid means that the selected cannabinoid is crystallized at alarger rate than other compounds within a cannabinoid solution (e.g.,other cannabinoids). For example, if CBD is selectively crystallizedfrom a cannabinoid solution containing CBD, THC, and CBG, a greaterproportion of the CBD in solution will be crystallized than theproportion of other cannabinoids in the solution. Applicant notes thatsmall amounts of non-selected cannabinoids are sometimes detected in thecrystals recovered from a solution, but the concentration of thesecannabinoids is greatly reduced after filtering and wash steps,suggesting that these non-selected cannabinoids were not crystallized,but were instead liquid contaminants on the surface of the selectedcannabinoid crystals.

II. Cannabis

Cannabis is a genus of flowering plants that includes three differentspecies, Cannabis sativa, Cannabis indica and Cannabis ruderalis. Thereare 483 identifiable chemical constituents known to exist in thecannabis plant (Rudolf Brenneisen (2007) in Marijuana and theCannabinoids, ElSohly, ed.; incorporated herein by reference), includingat least 85 different cannabinoids and over 120 terpenes (El-Alfy, AbirT, et al. (2010) Pharmacology Biochemistry and Behavior 95 (4): 434-42;incorporated herein by reference). The two most well-known cannabinoidsproduced by Cannabis plants are tetrahydrocannabinol (THC) andcannabidiol (CBD).

IIA. Cannabinoids

Cannabinoids are a unique family of terpeno-phenolic compounds producedby Cannabis plants. Typical cannabinoids isolated from Cannabis plantsinclude, but are not limited to, Cannabigerolic Acid (CBGA),Cannabigerolic Acid monomethylether (CBGAM), Cannabigerol (CBG),Cannabigerol monomethylether (CBGM), Cannabigerovarinic Acid (CBGVA),Cannabigerovarin (CBGV), Cannabichromenic Acid (CBCA), Cannabichromene(CBC), Cannabichromevarinic Acid (CBCVA), Cannabichromevarin (CBCV),Cannabidiolic Acid (CBDA), Cannabidiol (CBD), Cannabidiolmonomethylether (CBDM), Cannabidiol-C4 (CBD-C4), Cannabidivarinic Acid(CBDVA), Cannabidivarin (CBDV), Cannabidiorcol (CBD-C1),Tetrahydrocannabinolic acid A (THCA-A), Tetrahydrocannabinolic acid B(THCA-B), Tetrahydrocannabinolic Acid (THCA), Tetrahydrocannabinol(THC), Tetrahydrocannabinolic acid C4 (THCA-C4), TetrahydrocannabinolC4(THC-C4), Tetrahydrocannabivarinic acid (THCVA),Tetrahydrocannabivarin (THCV), Tetrahydrocannabinolic acid-C4(THCA-C4),Tetrahydrocannabinol-C1 (THC-C1), Δ7-cis-iso-tetrahydrocannabivarin,Δ8-tetrahydrocannabinolic acid (Δ8-THCA), Cannabivarinodiolic (CBNDVA),Cannabivarinodiol (CBNDV), Δ8-tetrahydrocannabinol (Δ8-THC),Δ9-tetrahydrocannabinol (Δ9-THC), Cannabicyclolic acid (CBLA),Cannabicyclol (CBL), Cannabicyclovarin (CBLV), Cannabielsoic acid A(CBEA-A), Cannabielsoic acid B (CBEA-B), Cannabielsoin (CBE),Cannabivarinselsoin (CBEV), Cannabivarinselsoinic Acid (CBEVA),Cannabielsoic Acid (CBEA), Cannabielvarinsoin (CBLV),Cannabielvarinsoinic Acid (CBLVA), Cannabinolic acid (CBNA), Cannabinol(CBN), Cannabivarinic Acid (CBNVA), Cannabinol methylether (CBNM),Cannabinol-C4 (CBN-C4), Cannabivarin (CBV), Cannabino-C2 (CBN-C2),Cannabiorcol (CBN-C1), Cannabinodiol (CBND), Cannabinodiolic Acid(CBNDA), Cannabinodivarin (CBDV), Cannabitriol (CBT),10-Ethoxy-9-hydroxy-Δ6a-tetrahydrocannabinol,8,9-Dihydroxy-Δ6a(10a)-tetrahydrocannabinol (8,9-Di-OH-CBT-C5),Cannabitriolvarin (CBTV), Ethoxy-cannabitriolvarin (CBTVE),Dehydrocannabifuran (DCBF), Cannbifuran (CBF), Cannabichromanon (CBCN),Cannabicitran (CBT), 10-Oxo-Δ6a(10a)-tetrahydrocannabinol (OTHC),Δ9-cis-tetrahydrocannabinol (cis-THC), Cannabiripsol (CBR),3,4,5,6-tetrahydro-7-hydroxy-alpha-alpha-2-trimethyl-9-n-propyl-2,6-methano-2H-1-benzoxocin-5-methanol(OH-iso-HHCV), Trihydroxy-delta-9-tetrahydrocannabinol (triOH-THC),Yangonin, Epigallocatechin gallate, Dodeca-2E, 4E, 8Z, 10Z-tetraenoicacid isobutylamide, and Dodeca-2E,4E-dienoic acid isobutylamide. SeeHolley et al. (1975) J. Pharm. Sci. 64:892-894 and De Zeeuw et al.(9172) Science 175:778-779, each of which is herein incorporated byreference in its entirety for all purposes.

Most cannabinoids exist in two forms, as acids and in neutral(decarboxylated) forms. The acid form is designated by an “A” at the endof its acronym (i.e. THCA). The phytocannabinoids are synthesized in theplant as acid forms, and while some decarboxylation does occur in theplant, it increases significantly post-harvest and the kinetics increaseat high temperatures. (Sanchez and Verpoorte 2008). Cannabinoids intheir acid forms (those ending in “-A”) can be converted to theirnon-acidic forms through a process called decarboxylation. While somedecarboxylation (e.g., neutralization) of cannabinoids does occur in theplant, production of the neutral forms increases significantlypost-harvest. (Sanchez and Verpoorte (2008) Plant Cell Physiol.December: 49(12)). Full decarboxylation of phytocannabinoids can becatalyzed by post-cultivation heating cannabis plant material orextracted cannabinoids (e.g., by combustion, vaporization, or baking inan oven).

In order to find the total amount of non-acidic cannabinoid, the totalmeasured content of acid cannabinoid variants forms should be adjustedto account for the loss of the carboxyl group. In some embodiments, thisadjustment can be made by multiplying the molar content of the acidiccannabinoid forms by the molecular weight of the correspondingdecarboxylated cannabinoid. Other shorthand conversions are alsoavailable for quickly converting acidic cannabinoid content to activecannabinoid content.

For example, in some embodiments, THCA can be converted to active THCusing the formula: THCA×0.877=THC. When using this approach, the maximumTHC for the sample is: THCmax=(THCA×0.877)+THC. This method has beenvalidated according to the principles of the International Conference onHarmonization. Similarly, CBDA can be converted to active CBD and theyield is determined using the yield formula: CBDA×0.877=CBD. Also, themaximum amount of CBD yielded, i.e. max CBD for the sample is:CBDmax=(CBDA×0.877)+CBD. Additionally, CBGA can be converted to activeCBG by multiplying CBGA by 0.878 (CBGmax=(CBGA×0.878)+CBG).

In some embodiments, provided herein are methods of selectivelycrystallizing and/or purifying a cannabinoid from a solution containinga plurality of cannabinoids. In some embodiments, any of thecannabinoids listed above may be selectively crystallized and/orpurified according to the methods of the disclosure. In someembodiments, cannabidiol (CBD), tetrahydrocannabinol (THC),tetrahydrocannabivarin (THCV), cannabidiolic acid (CBDA), cannabidivarin(CBDV), tetrahydrocannabinolic acid (THCA), cannabigerol (CBG),cannabigerolic acid (CBGA), cannabinol (CBN), cannabinolic acid (CBNA),cannabidivarinic acid (CBDVA), cannabichromenic acid (CBCA), orcannabichromene (CBC) are selectively crystallized and/or purifiedaccording to the methods of this disclosure.

Brief descriptions and chemical structures of the aforementionedcannabinoids are provided below.

Cannabidiol (CBD)

CBD is a cannabinoid found in Cannabis shown to display sedative effectsin animal tests (Pickens, (1981) Br. J. Pharmacol. 72 (4): 649-56). Someresearch, however, indicates that CBD can increase alertness, andattenuates the memory-impairing effect of THC. (Nicholson et al., June(2004) J Clin Psychopharmacol 24 (3): 305-13; Morgan et al., (2010) TheBritish Journal of Psychiatry, 197:258-290). CBD may also decrease therate of THC clearance from the body, perhaps by interfering with themetabolism of THC in the liver. Medically, CBD has been shown to relieveconvulsion, inflammation, anxiety, and nausea, as well as inhibit cancercell growth (Mechoulam, et al., 2007, Chemistry & Biodiversity 4 (8):1678-1692), for example reducing growth and invasiveness of aggressivehuman breast cancer cells (McAllister et al., 2007, Mol. Cancer Ther. 6(11): 2921-7) Recent studies have also shown CBD to be as effective asan atypical antipsychotic for treating schizophrenia (Zuardi et al.,2006, Braz. J. Med. Biol. Res. 39 (4): 421-429.), and studies alsosuggests that CBD may relieve symptoms of dystonia (Consroe, 1986, TheInternational journal of neuroscience 30 (4): 277-282).

Cannabis produces cannabidiolic acid (CBDA) through the same metabolicpathway as THC, until the last step, where CBDA synthase performscatalysis instead of THCA synthase. See Marks et al. (2009) Journal ofExperimental Botany 60 (13): 3715-3726.) and Meijer et al. I, II, III,and IV.

Non-limiting examples of CBD variants include CBD-05, CBDM-05, CBD-C4,CBDV-C3, CBD-C1, CBDA-05, and CBDVA-C3.

Tetrahydrocannabinol (THC)

Known as delta-9-tetrahydrocannabinol (Δ9-THC), THC is the principalpsychoactive constituent (or cannabinoid) of the Cannabis plant. THC hasmild to moderate analgesic effects, and Cannabis can be used to treatpain by altering transmitter release on dorsal root ganglion of thespinal cord and in the periaqueductal gray. Other effects includerelaxation, alteration of visual, auditory, and olfactory senses,fatigue, and appetite stimulation. THC has marked antiemetic properties,and may also reduce aggression in certain subjects (Hoaken (2003)Addictive Behaviors 28: 1533-1554).

The pharmacological actions of THC result from its partial agonistactivity at the cannabinoid receptor CB1, located mainly in the centralnervous system, and the CB2 receptor, mainly expressed in cells of theimmune system (Pertwee, (2006) International Journal of Obesity 30:S13-S18.) It is also suggested that THC has an anticholinesteraseaction, which may implicate it as a potential treatment for Alzheimer'sand Myasthenia gravis (Eubanks et al., (2006) Molecular Pharmaceutics 3(6): 773-7).

In the cannabis plant, THC occurs mainly as tetrahydrocannabinolic acid(THCA, 2-COOH-THC). Geranyl pyrophosphate and olivetolic acid react viaan enzyme-catalyzed reaction to produce cannabigerolic acid, which iscyclized by the enzyme THC acid synthase to give THCA. Over time, orwhen heated, THCA is decarboxylated producing THC.

Non-limiting examples of THC variants include Δ9-THC-C5, Δ9-THC-C4,Δ9-THCV-C3, Δ9-THCO-C1, Δ9-THCA-C5 A, Δ9-THCA-C5 B, Δ9-THCA-C4 A,Δ9-THCA-C4 B, Δ9-THCVA-C3 A, Δ9-THCOA-C1 A, Δ9-THCOA-C1 B, Δ8-THC-C5,Δ8-THCA-C5 A, (−)-cis-Δ9-THC-C5.

Tetrahydrocannabivarin (THCV)

THCV is a propyl analogue of tetrahydrocannabinol. Although THCVpossesses an almost identical structure to Δ9-THC (varying only by thelength of its lipophilic alkyl chain), it has different moleculartargets and pharmacological profile. Compared to THC which demonstratesits effects through weak partial agonist activity of bothendocannabinoid receptors Cannabinoid-1 (CB1R) and Cannabinoid-2 (CB2R),THCV acts as a CB1 antagonist and a partial agonist of CB2. THCV hasbeen reported to activate 5HT1A receptors to produce an antipsychoticeffect that has therapeutic potential for ameliorating some of thenegative, cognitive and positive symptoms of schizophrenia (Br JPharmacol. 2015 March; 172(5): 1305-1318.) THCV has also shownantiepileptiform and anticonvulsant properties that suggest possibletherapeutic application in the treatment of pathophysiologichyperexcitability states such as untreatable epilepsy (Epilepsia. 2010August; 51(8):1522-32.).

Cannabidiolic Acid (CBDA)

CBDA is most abundant in the glandular trichromes on Cannabis buds. CBDAis the chemical precursor to CBD. CBDA has been shown to exerttherapeutic effects, including antiemetic, anti-inflammatory,anxiolytic, and antidepressant effects. (Behav Pharmacol. 2020September; 31(6):591-596.) An in vivo rodent study showed that CBDAreduces thermal pain sensitivity in a model of Rett syndrome.(Neuroscience. 2021 Jan. 15; 453, 113-123.)

Cannabidivarin (CBDV)

CBDV is a non-psychoactive cannabinoid found in Cannabis. It is ahomolog of CBD with the side-chain shortened by two methylene bridges(CH2 units). CBDV has demonstrated anticonvulsant activity in animalmodels and in human clinical trials. (Br J Pharmacol. 2013 October;170(3):679-92.) CBDV also acts as a functional partial agonist ondopamine D2-like receptors in vivo, supporting its therapeutic use inneurological disorders. (Biochemical and Biophysical ResearchCommunications. 2020; 533(4):1366-1370.).

Tetrahydrocannabinolic Acid (THCA)

THCA is found in variable quantities in fresh, undried Cannabis, but isprogressively decarboxylated to THC with drying and heating. THCA isproduced from cannabigerolic acid by THCA synthase. THCA has been shownto have anti-inflammatory properties. (Biol Pharm Bull. 2011;34(5):774-8.).

Cannabigerol (CBG)

CBG is a non-psychoactive cannabinoid found in the Cannabis plants. CBGhas been found to act as a high affinity α2-adrenergic receptor agonist,moderate affinity 5-HT1A receptor antagonist, and low affinity CB1receptor antagonist. It also binds to the CB2 receptor. Cannabigerol hasalso been shown to reduce depression in animal models (US PatentApplication Publication No. 2008-0031977). In particular, CBG has beenshown to have significant potential applications in the treatment ofglaucoma, depression, Huntington's disease, MRSA, cachexia, and cancer(Craig et al. 1984, Experimental eye research 39 (3):251-259; U.S. Pat.No. 8,481,085; Valdeolivas et al. 2015, Neurotherapeutics January12(1):185-99; Appendino G et al., 2008, J. Nat Prod. August:71(8):1427-30; Borrelli F et al. 2013, Biochem Pharmacol May1:85(9):1306-16; Borrelli F. et al. 2014, Carcinogenesis December:35(12):2787-97) Non-limiting examples of CBG variants include(E)-CBG-C5, (E)-CBGM-C5 A, (Z)-CBGA-C5 A, (E)-CBGV-C3, (E)-CBGA-C5 A,(E)-CBGAM-C5 A, and (E)-CBGVA-C3 A.

Cannabigerolic Acid (CBGA)

CBGA is the acidic form of CBG. CBGA is synthesized from olivetolic acidand geranyl diphosphate. CBGA is a precursor to THCA, CBDA, and CBCA.CBGA has been found to inhibit aldose reductase activity, suggestingthat it may have therapeutic value for treatment of complications ofdiabetes. (Fitoterapia. 2018 June; 127:101-108.).

Cannabinol (CBN)

CBN is a mildly psychoactive cannabinoid found in trace amounts inCannabis. CBN is a metabolite of THC. CBN has been shown to havesignificant applications in the treatment of anxiety disorder, insomnia,inflammation, convulsions, and bacterial infections. (Herring et al.Journal of Pharmacology and Experimental Therapeutics December 1999, 291(3) 1156-1163.) CBN may be produced by aromatizing THC.

Cannabinolic Acid (CBNA)

CBNA is found in trace amounts in Cannabis. CBNA is produced from THCAafter exposure to ultraviolet light. CBNA has therapeutic benefit fortreatment of insomnia, convulsions, and chronic pain.

Cannabidivarinic Acid (CBDVA)

CBDVA is the acidic form of CBDV. Extracts containing CBDVA exhibitantioxidant and antimicrobial activity against methicillin-resistantstrains of Staphylococcus aureus. (Phytother Res. 2021 February;35(2):1099-1112.).

Cannabichromenic Acid (CBCA)

CBCA is the acidic form of CBC. CBCA is produced from CBGA. Geranylpyrophosphate and olivetolic acid combine to produce CBGA, which iscyclized by the enzyme CBCA synthase to form CBCA. In vitro studies showthat CBCA has more potent bactericidal activity than vancomycin, thecurrently recommended treatment for methicillin-resistant Staphylococcusaureus infections. (Antibiotics 2020, 9(8), 523).

Cannabichromene (CBC)

CBC is produced from decarboxylation of CBCA. CBC is an agonist of TRPA1and less potently an agonist of TRPV3 and TRPV4. CBC inhibits nitricoxide production in macrophages and ameliorates murine colitis. (Br JPharmacol. 2013 May; 169(1): 213-229; Acta Physiol (Oxf). 2012 February;204(2):255-66.).

IIB. Additional Components of Cannabis

In addition to cannabinoids, Cannabis also comprises non-specificlipid-soluble material or “ballast” e.g. waxes, wax esters andglycerides, unsaturated fatty acid residues, terpenes, chlorophyll,carotenes, flavonoids, pigments, sugars, cellulose compounds, andminerals.

Cannabis produces over 120 different terpenes (Russo (2011) BritishJournal of Pharmacology, 163:1344-1364). Within the context and verbiageof this document the terms ‘terpenoid’ and ‘terpene’ are usedinterchangeably. In some embodiments, the present disclosure providescompositions comprising one or more terpenes or terpenoids.

In addition to many circulatory and muscular effects, some terpenesinteract with neurological receptors. A few terpenes produced bycannabis plants also bind weakly to cannabinoid receptors. Some terpenescan alter the permeability of cell membranes and allow in either more orless THC, while other terpenes can affect serotonin and dopaminechemistry as neurotransmitters. Terpenoids are lipophilic, and caninteract with lipid membranes, ion channels, a variety of differentreceptors (including both G-protein coupled odorant and neurotransmitterreceptors), and enzymes. Some are capable of absorption through humanskin and passing the blood brain barrier.

Terpenoids are mainly synthesized in two metabolic pathways: mevalonicacid pathway (a.k.a. HMG-CoA reductase pathway, which takes place in thecytosol) and MEP/DOXP pathway (a.k.a. The 2-C-methyl-D-erythritol4-phosphate/1-deoxy-D-xylulose 5-phosphate pathway, non-mevalonatepathway, or mevalonic acid-independent pathway, which takes place inplastids). Geranyl pyrophosphate (GPP), which is used by cannabis plantsto produce cannabinoids, is formed by condensation of dimethylallylpyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP) via thecatalysis of GPP synthase. Alternatively, DMAPP and IPP are ligated byFPP synthase to produce farnesyl pyrophosphate (FPP), which can be usedto produce sesquiterpenoids. Geranyl pyrophosphate (GPP) can also beconverted into monoterpenoids by limonene synthase.

Terpenes are derived biosynthetically from units of isoprene, which havethe molecular formula C₅H₈. The basic molecular formulae of terpenes aremultiples of (C₅H₈)_(n) where n is the number of linked isoprene units.The isoprene units may be linked together “head to tail” to form linearchains or they may be arranged to form rings.

Within the context of this disclosure, the term “terpene” includesHemiterpenes, Monoterpenols, Terpene esters, Diterpenes, Monoterpenes,Polyterpenes, Triterpenes, Tetraterpenes, Terpenoid oxides,Sesterterpenes, Sesquiterpenes, Norisoprenoids, as well as theirisomers, enantiomers, or derivatives. Within the context of thisdisclosure, the term terpene includes the α-(alpha), β-(beta),γ-(gamma), oxo-, isomers, or any combinations thereof.

In some embodiments, the present disclosure teaches separating aselected cannabinoid from a solution comprising terpenes. Non-limitingexamples of terpenes include: Alpha Pinene, Limonene, Beta Pinene, AlphaPhellandrene, Terpinolene, Nerolidol, Nerol, Myrcene, BetaCaryophyllene, 7,8-dihydro-alpha-ionone, 7,8-dihydro-beta-ionone,Acetanisole, Acetic Acid, Acetyl Cedrene, Anethole, Anisole,Benzaldehyde, Bergamotene (Alpha-cis-Bergamotene)(Alpha-trans-Bergamotene), Bisabolol (Beta-Bisabolol), Alpha Bisabolol,Borneol, Bornyl Acetate, Butanoic/Butyric Acid, Cadinene(Alpha-Cadinene) (Gamma-Cadinene), Cafestol, Caffeic acid, Camphene,Camphor, Capsaicin, Carene (Delta-3-Carene), Carotene, Carvacrol,Dextro-Carvone, Laevo-Carvone, Alpha-Caryophyllene, Beta-Caryophyllene,Caryophyllene oxide, Cedrene (Alpha-Cedrene) (Beta-Cedrene), CedreneEpoxide (Alpha-Cedrene Epoxide), Cedrol, Cembrene, Chlorogenic Acid,Cinnamaldehyde, Alpha-amyl-Cinnamaldehyde, Alpha-hexyl-Cinnamaldehyde,Cinnamic Acid, Cinnamyl Alcohol, Citronellal, Citronellol, Cryptone,Curcumene (Alpha-Curcumene) (Gamma-Curcumene), Decanal,Dehydrovomifoliol, Diallyl Disulfide, Dihydroactinidiolide, DimethylDisulfide, Eicosane/Icosane, Elemene (Beta-Elemene), Estragole, Ethylacetate, Ethyl Cinnamate, Ethyl maltol, Eucalyptol/1,8-Cineole, Eudesmol(Alpha-Eudesmol) (Beta-Eudesmol) (Gamma-Eudesmol), Eugenol, Euphol,Farnesene, Farnesol, Fenchol (Beta-Fenchol), Fenchone, Geraniol, Geranylacetate, Germacrenes, Germacrene B, Guaia-1(10),11-diene, Guaiacol,Guaiene (Alpha-Guaiene), Gurjunene (Alpha-Gurjunene), Herniarin,Hexanaldehyde, Hexanoic Acid, Humulene (Alpha-Humulene) (Beta-Humulene),Ionol (3-oxo-alpha-ionol) (Beta-Ionol), Ionone (Alpha-Ionone)(Beta-Ionone), Ipsdienol, Isoamyl Acetate, Isoamyl Alcohol, IsoamylFormate, Isoborneol, Isomyrcenol, Isopulegol, Isovaleric Acid, Isoprene,Kahweol, Lavandulol, Limonene, Gamma-Linolenic Acid, Linalool,Longifolene, Alpha-Longipinene, Lycopene, Menthol, Methyl butyrate,3-Mercapto-2-Methylpentanal, Mercaptan/Thiols, Beta-Mercaptoethanol,Mercaptoacetic Acid, Allyl Mercaptan, Benzyl Mercaptan, Butyl Mercaptan,Ethyl Mercaptan, Methyl Mercaptan, Furfuryl Mercaptan, EthyleneMercaptan, Propyl Mercaptan, Thenyl Mercaptan, Methyl Salicylate,Methylbutenol, Methyl-2-Methylvalerate, Methyl Thiobutyrate, Myrcene(Beta-Myrcene), Gamma-Muurolene, Nepetalactone, Nerol, Nerolidol, Nerylacetate, Nonanaldehyde, Nonanoic Acid, Ocimene, Octanal, Octanoic Acid,P-Cymene, Pentyl butyrate, Phellandrene, Phenylacetaldehyde,Phenylethanethiol, Phenylacetic Acid, Phytol, Pinene, Beta-Pinene,Propanethiol, Pristimerin, Pulegone, Quercetin, Retinol, Rutin,Sabinene, Sabinene Hydrate, cis-Sabinene Hydrate, trans-SabineneHydrate, Safranal, Alpha-Selinene, Alpha-Sinensal, Beta-Sinensal,Beta-Sitosterol, Squalene, Taxadiene, Terpin hydrate, Terpineol,Terpine-4-ol, Alpha-Terpinene, Gamma-Terpinene, Terpinolene, Thiophenol,Thuj one, Thymol, Alpha-Tocopherol, Tonka Undecanone, Undecanal,Valeraldehyde/Pentanal, Verdoxan, Alpha-Ylangene, Umbelliferone, andVanillin.

In some embodiments, the methods of the disclosure comprise separating aselected cannabinoid from a derivative of a terpene. Derivatives ofterpenes include terpenoids, hemiterpenoids, monoterpenoids,sesquiterpenoids, sesterterpenoid, sesquarterpenoids, tetraterpenoids,triterpenoids, tetraterpenoids, polyterpenoids, isoprenoids, andsteroids. Terpenoids, a.k.a. isoprenoids, are a large and diverse classof naturally occurring organic chemicals similar to terpenes, derivedfrom five-carbon isoprene units assembled and modified in thousands ofways. Non-limiting examples of terpenoids include, Hemiterpenoids, 1isoprene unit (5 carbons); Monoterpenoids, 2 isoprene units (10C);Sesquiterpenoids, 3 isoprene units (15C); Diterpenoids, 4 isoprene units(20C) (e.g. ginkgolides); Sesterterpenoids, 5 isoprene units (25C);Triterpenoids, 6 isoprene units (30C) (e.g. sterols); Tetraterpenoids, 8isoprene units (40C) (e.g. carotenoids); and Polyterpenoid with a largernumber of isoprene units.

In some embodiments, the methods of the disclosure comprise selectivelycrystallizing and/or purifying a selected cannabinoid from a solutioncomprising any of the aforementioned additional components of Cannabis.

III. Methods of Selectively Crystallizing and/or Purifying a SelectedCannabinoid from a Cannabinoid Solution

In some embodiments, provided herein are methods of selectivelycrystallizing and/or purifying a selected cannabinoid from a cannabinoidsolution. In some embodiments, the solution comprises a plurality ofcannabinoids. In some embodiments, the selected cannabinoid is the onlycannabinoid in the solution.

In some embodiments, the methods of the disclosure comprisecrystallizing or extracting and/or purifying a selected cannabinoid froma solution containing a plurality of cannabinoids. In some embodiments,the solution containing a plurality of cannabinoids refers to a solutioncontaining two or more cannabinoids. For example, the solutioncontaining a plurality of cannabinoids may contain at least two, atleast three, at least four, at least five, at least six, at least seven,at least eight, at least nine, at least ten, at least 11, at least 12,at least 13, at least 14, at least 15, at least 16, at least 17, atleast 18, at least 19, at least 20, at least 21, at least 22, at least23, at least 24, at least 25, at least 26, at least 27, at least 28, atleast 29, or at least 30 cannabinoids, or any value or rangetherebetween, including endpoints. The solution containing a pluralityof cannabinoids may contain any of the cannabinoids described herein,for example, those described in Section IIA of this disclosure. In someembodiments, the selected cannabinoid is selected from the groupconsisting of CBD, THC, THCV, CBDA, CBDV, THCA, CBG, CBN, CBNA, CBDVA,CBCA, and CBC.

The solution containing a plurality of cannabinoids may be a Cannabisoil. As used herein the term “Cannabis oil,” which is usedinterchangeably herein with “Hemp oil,” refers to a composition producedby extracting cannabinoids from a Cannabis plant or Cannabis plantpart(s). In some embodiments, the Cannabis oil is a primary cannabinoidextract (also referred to as a “primary cannabis extract”). In someembodiments, the primary cannabinoid extract is substantially free ofany exogenous solvent. That is, in some embodiments, the cannabisoil/primary cannabinoid extract comprises less than 5%, 4%, 3%, 2%, 1%,0.5%, 0.3%, 0.2%, or 0.1% of an exogenous solvent. In some embodiments,the primary cannabinoid extract is the chemical constituents of Cannabis(e.g., cannabinoids and terpenes) suspended in MCT derived from theCannabis plant. In some embodiments, the primary cannabis extract is aCO2 extraction or an alcohol extraction of a cannabis plant. In someembodiments, the primary cannabis extract is a CO2 extraction or analcohol extraction of a cannabinoid-producing microorganism culture.

In some embodiments, a “selected cannabinoid” is present in the solutioncontaining a plurality of cannabinoids at a concentration greater thanor equal to its supersaturation point. The term “supersaturation point”is the point at which the cannabinoid's amount in solution (e.g.,concentration) exceeds its solubility at a given temperature. In someembodiments, the supersaturation point of the selected cannabinoid isgreater than or equal to 20%, 25%, 30%, 40%, or 50% by weight of thesolution. For example, the supersaturation point of the selectedcannabinoid is greater than or equal to 55%, greater than or equal to60%, greater than or equal to 65%, greater than or equal to 70%, greaterthan or equal to 75%, greater than or equal to 80%, greater than orequal to 85%, greater than or equal to 90%, or greater than or equal to95% by weight of the solution. In some embodiments, the supersaturationpoint of the selected cannabinoid is from about 50% and about 70% byweight of the solution. For example, the supersaturation point of theselected cannabinoid is about 50%, about 51%, about 52%, about 53%,about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%,about 67%, about 68%, about 69%, or about 70% by weight of the solution,including all values and subranges in between inclusive of endpoints. Insome embodiments, the supersaturation point of the selected cannabinoidis between about 50% and about 60% by weight of the solution. In someembodiments, the supersaturation point of the selected cannabinoid isbetween about 60% and about 70% by weight of the solution.

In some embodiments, the selected cannabinoid is present at a minimumconcentration in the solution containing a plurality of cannabinoids orin a solution in which the selected cannabinoid is the only cannabinoid.The term “minimum concentration” refers to the lowest concentration ofcannabinoid required for selective crystallization of the cannabinoid.

In some embodiments, the minimum concentration of a selected cannabinoidin a solution is from 1% to 90% by weight of the solution. For example,the minimum concentration of a selected cannabinoid in a solution isabout 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%,about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%,about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%,about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%,about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%,about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%,about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%,about 86%, about 87%, about 88%, about 89%, or about 90% by weight ofthe solution. In some embodiments, the minimum concentration of aselected cannabinoid in a solution is from 5% to 30% by weight of thesolution. In some embodiments, the minimum concentration of a selectedcannabinoid in a solution containing a plurality of cannabinoids is from10% to 75%. In some embodiments, the minimum concentration of a selectedcannabinoid in a solution is about 5% by weight of the solution. In someembodiments, the minimum concentration of a selected cannabinoid isabout 10% by weight of the solution. In some embodiments, the minimumconcentration of a selected cannabinoid in a solution is about 25% byweight of the solution. In some embodiments, the minimum concentrationof a selected cannabinoid in a solution is about 19.6% by weight of thesolution.

In some embodiments, the selected cannabinoid is the highestconcentration cannabinoid in the solution containing a plurality ofcannabinoids. For example, CBD is the selected cannabinoid in a solutioncomprising 70% w/w CBD, 5% w/w CBN, and 2% w/w THC.

In some embodiments, the selected cannabinoid is present in the solutionat a concentration from about 0.5% to about 99% by weight of thesolution. For example, the selected cannabinoid may be present at aconcentration of about 0.5%, about 0.6%, about 0.7%, about 0.8%, about0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%,about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, about 10%,about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%,about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%,about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%,about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%,about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about69%, or about 70%, about 75%, about 80%, about 85%, about 90%, about95%, about 96%, about 97%, about 98%, or about 99% by weight of thesolution, including all subranges and ranges therebetween. In someembodiments, the selected cannabinoid is present at a concentration ofat least about 0.5%, at least about 0.6%, at least about 0.7%, at leastabout 0.8%, at least about 0.9%, at least about 1%, at least about 1.5%,at least about 2%, at least about 2.5%, at least about 3%, at leastabout 3.5%, at least about 4%, at least about 4.5%, at least about 5%,at least about 5.5%, at least about 6%, at least about 6.5%, at leastabout 7%, at least about 7.5%, at least about 8%, at least about 8.5%,at least about 9%, at least about 9.5%, at least about 10%, at leastabout 11%, at least about 12%, at least about 13%, at least about 14%,at least about 15%, at least about 16%, at least about 17%, at leastabout 18%, at least about 19%, at least about 20%, at least about 21%,at least about 22%, at least about 23%, at least about 24%, at leastabout 25%, at least about 26%, at least about 27%, at least about 28%,at least about 29%, at least about 30%, at least about 31%, at leastabout 32%, at least about 33%, at least about 34%, at least about 35%,at least about 36%, at least about 37%, at least about 38%, at leastabout 39%, at least about 40%, at least about 41%, at least about 42%,at least about 43%, at least about 44%, at least about 45%, at leastabout 46%, at least about 47%, at least about 48%, at least about 49%,at least about 50%, at least about 51%, at least about 52%, at leastabout 53%, at least about 54%, at least about 55%, at least about 56%,at least about 57%, at least about 58%, at least about 59%, at leastabout 60%, at least about 61%, at least about 62%, at least about 63%,at least about 64%, at least about 65%, at least about 66%, at leastabout 67%, at least about 68%, at least about 69%, or at least about70%, at least about 75%, at least about 80%, at least about 85%, atleast about 90%, at least about 95%, at least about 96%, at least about97%, at least about 98%, or at least about 99% by weight of thesolution, including all ranges and subranges therebetween. In someembodiments, the selected cannabinoid is present in the solution at aconcentration from about 0.5% to about 10% by weight of the solution. Insome embodiments, the selected cannabinoid is present in the solution ata concentration between about 10% and about 70% by weight of thesolution. In some embodiments, the selected cannabinoid is present inthe solution at a concentration between about 10% and about 50% byweight of the solution. In some embodiments, the selected cannabinoid ispresent in the solution at a concentration from about 50% to about 70%by weight of the solution. In some embodiments, the selected cannabinoidis present in the solution at a concentration of at least 10% by weightof the solution. In some embodiments, the selected cannabinoid ispresent in the solution at a concentration of at least 50% by weight ofthe solution. In some embodiments, the selected cannabinoid is presentin the solution containing a plurality of cannabinoids at aconcentration of at least 60% by weight of the solution. In someembodiments, the selected cannabinoid is present in the solution at aconcentration of at least about 70% by weight of the solution.

In some embodiments, the selected cannabinoid is soluble in the solution(e.g., a primary cannabinoid extract) when the Hildebrand solubilityparameter of the selected cannabinoid is less than 5.1 MPa^(1/2) of theHildebrand solubility parameter of the solvent (e.g., MCT). In someembodiments, the selected cannabinoid is soluble in the primarycannabinoid extract when it is heated to a temperature between 50° C.and about 79° C., and insoluble in the primary cannabinoid extract attemperatures less than 50° C. The Hildebrand solubility parameters forexemplary compounds present in Cannabis are provided in Table 1. TheHildebrand solubility parameters are described in detail in Hansen,Charles M, Hansen Solubility Parameters, A User's Handbook, CRC Press,2000, which is incorporated by reference herein in its entirety.

TABLE 1 Hildebrand Solubility Parameters for Cannabinoids and TerpenesSolubility Solubility Parameter Parameter Compound (MPa^(1/2)) Compound(MPa^(1/2)) THC 22.09 Beta-caryophyllene 21.41 CBD 24.34 D-limonene24.46 THCA 24.14 Pulegone 25.65 CBDA 25.77 1,8-cineole 18.96Beta-myrcene 21.46 alpha-terpineol 17.10 Beta-sitosterol 3.86Terpineol-4-ol 18.21 Limonene 16.90 Apigenin 20.80 Alpha-pinene 16.16Quercetin 25.89 p-cymene 16.57 Cannflavin A 10.35

In some embodiments, the solution comprises non-specific lipid-solublematerial or “ballast” e.g. waxes, wax esters and glycerides, unsaturatedfatty acid residues, terpenes, carotenes, chlorophyll, flavonoids,pigments, sugars, cellulose compounds, and minerals.

In some embodiments, the solution is a Cannabis oil that does notcontain any cutting agents. Examples of cutting agents includepolyethylene glycol and glycerin.

In some embodiments, the solution comprises an organic non-polarsolvent. In some embodiments, the organic non-polar solvent is oleicacid, olive oil, coconut oil, canola oil, flaxseed oil, avocado oil,sesame oil, canola oil, palm oil, safflower oil, soybean oil, corn oil,peanut oil, walnut oil, flaxseed oil, sunflower oil, palm oil, palmkernel oil, caproic acid, caprylic acid, hempseed oil, walnut oil, ormedium-chain triglyceride (MCT) oil.

In some embodiments, the methods of the disclosure, (e.g., the methodsof Sections IIIA and IIIB) do not use toxic solvents, such as pentane,hexane, ethanol, ether, isopropanol, propane, or butane. In someembodiments, the methods of the disclosure are zero waste processes.

IIIA. Method of Selectively Crystallizing a Selected Cannabinoid from aSolution

In some embodiments, provided herein is a method of crystallizing aselected cannabinoid from a cannabinoid solution, comprising: (a)providing a solution containing a substantially dissolved selectedcannabinoid comprising microbubbles or dissolved air; and (b) exposingthe dissolved cannabinoid solution of step (a) to a vacuum for a timeperiod sufficient to crystallize the selected cannabinoid. In someembodiments, the solution containing a substantially dissolvedcannabinoid is produced by increasing the temperature of the cannabinoidsolution until the selected cannabinoid is substantially dissolved inthe solution. In some embodiments, the vacuum is greater than about −5inHg, about −10 inHg, about −15 inHg, about −20 inHg, or about −25 inHg.Without being bound by theory, exposure of the cannabinoid solution to avacuum allows microbubbles or dissolved air to expand, facilitatingnucleation of crystals of the selected cannabinoid. FIG. 17A showsexpansion of microbubbles after exposure to a vacuum.

In some embodiments, provided herein is a method of crystallizing aselected cannabinoid from a cannabinoid solution, comprising: (a)providing a solution containing a substantially dissolved selectedcannabinoid; and (b) exposing the dissolved cannabinoid solution of step(a) to a (e.g., one or more) nucleation factor(s) for a time periodsufficient to crystallize the selected cannabinoid, wherein thenucleation factor is selected from the group consisting of vacuum, coldshock, introducing a crystal of the selected cannabinoid into thedissolved cannabinoid solution (seed crystal), mechanically agitatingthe dissolved cannabinoid solution, and combinations thereof. In someembodiments, the solution containing a substantially dissolvedcannabinoid is produced by increasing the temperature of the cannabinoidsolution until the selected cannabinoid is substantially dissolved inthe solution. In some embodiments, vacuum is one of the nucleationfactors, and other nucleation factors precede the vacuum.

In some embodiments, provided herein is a method of crystallizing aselected cannabinoid from a cannabinoid solution, comprising: (a)providing a cannabinoid solution containing a substantially dissolvedselected cannabinoid, wherein the selected cannabinoid is present in thesolution at a concentration greater than or equal to its supersaturationpoint, and wherein the selected cannabinoid is the highest concentrationcannabinoid in the solution, and wherein said solution is substantiallyfree of any exogenous solvent; and (b) exposing the cannabinoid solutionof step (a) to nucleation factors comprising mechanical agitationfollowed by a vacuum for a time period sufficient to crystallize theselected cannabinoid. In some embodiments, the solution containing asubstantially dissolved cannabinoid is produced by increasing thetemperature of the cannabinoid solution until the selected cannabinoidis substantially dissolved in the solution. In some embodiments, thevacuum is greater than about −5 inHg, about −10 inHg, about −15 inHg,about −20 inHg, or about −25 inHg. Without being bound by theory,exposure of the cannabinoid solution to agitation allows microbubbles toform in the cannabinoid solution and exposure of the solution to avacuum allows the microbubbles to expand, facilitating nucleation ofcrystals of the selected cannabinoid.

In some embodiments, provided herein is a method of selectivelycrystallizing a selected cannabinoid from a solution of cannabinoids,comprising the steps of: (a) providing a solution containing a pluralityof cannabinoids, wherein the selected cannabinoid is present in thesolution at a concentration greater than or equal to its supersaturationpoint, and wherein the selected cannabinoid is the highest concentrationcannabinoid in the solution; (b) increasing the temperature of thesolution until the selected cannabinoid is substantially dissolved inthe solution; and (c) decreasing the temperature of the solution toabout −5° C. or lower to produce a cooled solution wherein the selectedcannabinoid crystallizes out of solution, thereby forming crystals ofthe selected cannabinoid. In some embodiments, the cooled solution isexposed to a vacuum.

In some embodiments, provided herein is a method of selectivelycrystallizing a selected cannabinoid from a solution of cannabinoids,comprising the steps of: (a) providing a solution containing a pluralityof cannabinoids, wherein the selected cannabinoid is present in thesolution at a concentration greater than or equal to 5%, 10%, 20%, or30% by weight of the solution, (b) increasing the temperature of thesolution until the selected cannabinoid is substantially dissolved inthe solution; and (c) decreasing the temperature of the solution toabout −5° C. or lower to produce a cooled solution wherein the selectedcannabinoid crystallizes out of solution, thereby forming crystals ofthe selected cannabinoid. In some embodiments, the cooled solution isexposed to a vacuum. In some embodiments, the selected cannabinoid ispresent in the solution at a concentration of greater than or equal to10% by weight of the solution.

In some embodiments, provided herein is a method of selectivelycrystallizing a selected cannabinoid from a solution of cannabinoids,comprising the steps of: (a) providing a solution containing a pluralityof cannabinoids, (b) increasing the temperature of the solution untilthe selected cannabinoid is substantially dissolved in the solution; and(c) decreasing the temperature of the solution to about −5° C. or lowerto produce a cooled solution wherein the selected cannabinoidcrystallizes out of solution, thereby forming crystals of the selectedcannabinoid, wherein the selected cannabinoid is present at a minimumconcentration of between 10% by weight and 95% by weight of thesolution. In some embodiments, the selected cannabinoid is present at aminimum concentration of about 10%, about 15%, or about 20%. In someembodiments, the cooled solution is exposed to a vacuum.

In some embodiments, provided herein is a method of crystallizating aselected cannabinoid from a solution in which the selected cannabinoidis the only cannabinoid in the solution, comprising the steps of (a)providing a solution containing the selected cannabinoid; (b) increasingthe temperature of the solution until the selected cannabinoid issubstantially dissolved in the solution; and (c) decreasing thetemperature of the solution to about −5° C. or lower to produce a cooledsolution wherein the selected cannabinoid crystallizes out of solution,thereby forming crystals of the selected cannabinoid. In someembodiments, the selected cannabinoid is present at a minimumconcentration of between 5% and 95% by weight of the solution. In someembodiments, the selected cannabinoid is present at a minimumconcentration of between 5 and 30% by weight of the solution.

Providing a Solution Containing a Substantially Dissolved Cannabinoid

In some embodiments, the method comprises providing a cannabinoidsolution. In some embodiments, the solution contains a substantiallydissolved cannabinoid. A cannabinoid that is substantially dissolved isat least 95% dissolved, at least 96% dissolved, at least 97% dissolved,at least 98% dissolved, at least 99% dissolved, or 100% dissolved. Theamount of cannabinoid dissolved may be determined using methods known toa person of skill in the art. In some embodiments, the amount ofcannabinoid dissolved is determined using a method selected from thegroup consisting of mass spectrometry, liquid chromatography,ultraviolet spectrophotometry, high performance liquid chromatography,ultraviolet-visible (UV-visible) absorption spectroscopy, andimmunoassay. In some embodiments, a solution containing a substantiallydissolved cannabinoid is clear (i.e., not opaque or occluded bycrystals). In some embodiments, the amount of cannabinoid dissolved isdetermined using a turbidity measurement.

In some embodiments, temperature of the solution is increased until theselected cannabinoid is substantially dissolved in the solution. In someembodiments however, the cannabinoids are already dissolved, and theheating step can be omitted. Without being bound by theory, heating thesolution breaks apart any existing cannabinoid crystals, to allow forthe formation of crystals that are homogenous in lattice structure,which in turn aids in purification/separation of the selectedcannabinoid.

In some embodiments, the temperature is increased to between about 50°C. and about 79° C., for example, about 50° C., about 51° C., about 52°C., about 53° C., about 54° C., about 55° C., about 56° C., about 57°C., about 58° C., about 59° C., about 60° C., about 61° C., about 62°C., about 63° C., about 64° C., about 65° C., about 66° C., about 67°C., about 68° C., about 69° C., about 70° C., about 71° C., about 72°C., about 73° C., about 74° C., about 75° C., about 76° C., about 77°C., about 78° C., or about 79° C., including all ranges and subrangestherebetween. In some embodiments, the temperature is increased to atleast about 50° C., 51° C., 52° C., 53° C., 54° C., 55° C., 56° C., 57°C., 58° C., 59° C., 60° C., 61° C., 62° C., 63° C., 64° C., 65° C., 66°C., 67° C., 68° C., 69° C., 70° C., 71° C., 72° C., 73° C., 74° C., 75°C., 76° C., 77° C., 78° C., 79° C., or 80° C., including all ranges thesubranges therebetween. In some embodiments, the temperature isincreased to about 60° C. In some embodiments, the selected cannabinoidis CBD, THC, THCV, CBDA, CBDV, THCA, CBG, CBGA, CBNA, CBDVA, CBCA, orCBC, and the temperature is increased to about 60° C. In someembodiments, the temperature is increased to about 70° C. In someembodiments, the temperature is increased to about 70° C., and theselected cannabinoid is CBN or CBNA.

Persons having skill in the art will be aware of the consequences ofoverheating cannabinoid oils. For example, in some embodiments, heatinga cannabis oil beyond 70° C., 71° C., 72° C., 73° C., 74° C., 75° C.,76° C., 77° C., 78° C., 79° C., or 80° C. for an extended period of timecan cause breakdown of component ingredients that may give the oil andsubsequent purified cannabinoids an undesirable color or taste.Therefore, in some embodiment, the cannabinoid oil is not heated beyond70° C., 71° C., 72° C., 73° C., 74° C., 75° C., 76° C., 77° C., 78° C.,79° C., or 80° C. for more than 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73,74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90minutes.

In some embodiments, the temperature is increased by about 1° C. everyminute, every 5 minutes, every 10 minutes, every 15 minutes, every 20minutes, every 30 minutes, or every hour. In some embodiments, thetemperature of the solution is increased by about 5° C. every minute,every 5 minutes, every 10 minutes, every 15 minutes, every 20 minutes,every 30 minutes, or every hour. In some embodiments, the temperature ofthe solution is increased by about 10° C. every minute, every 5 minutes,every 10 minutes, every 15 minutes, every 20 minutes, every 30 minutes,or every hour. In some embodiments, the temperature of the solution isincreased by about 15° C. every minute, every 5 minutes, every 10minutes, every 15 minutes, every 20 minutes, every 30 minutes, or everyhour. In some embodiments, the temperature of the solution is increasedby about 20° C. every minute, every 5 minutes, every 10 minutes, every15 minutes, every 20 minutes, every 30 minutes, or every hour. In someembodiments, the temperature of the solution is increased by about 30°C. every minute, every 5 minutes, every 10 minutes, every 15 minutes,every 20 minutes, every 30 minutes, or every hour. In some embodiments,the temperature of the solution is increased by about 40° C. everyminute, every 5 minutes, every 10 minutes, every 15 minutes, every 20minutes, every 30 minutes, or every hour. In some embodiments, thetemperature of the solution is increased by about 50° C. every minute,every 5 minutes, every 10 minutes, every 15 minutes, every 20 minutes,every 30 minutes, or every hour.

In some embodiments, the temperature is increased using a thermalcycler.

In some embodiments, the solution is stirred or mixed during heating.

The solution may comprise any of the features described in Section IIIof this disclosure. As used herein, the “selected cannabinoid” is thecannabinoid that is crystallized from the solution, such as a solutioncontaining a plurality of cannabinoids or a solution in which thecannabinoid is the only cannabinoid in the solution. In someembodiments, the selected cannabinoid is selected from the groupconsisting of cannabidiol (CBD), tetrahydrocannabinol (THC),tetrahydrocannabivarin (THCV), cannabidiolic acid (CBDA), cannabigerolicacid (CBGA), cannabidivarin (CBDV), tetrahydrocannabinolic acid (THCA),cannabigerol (CBG), cannabinol (CBN), cannabinolic acid (CBNA),cannabidivarinic acid (CBDVA), cannabichromenic acid (CBCA), andcannabichromene (CBC).

In some embodiments, the selected cannabinoid is present in the solutionwherein at least one of the cannabinoids is at a concentration greaterthan or equal to its supersaturation point. Table 1 contains thesupersaturation points of exemplary cannabinoids.

Exposure to Nucleation Factors

In some embodiments, a solution containing a substantially dissolvedcannabinoid is exposed to one or more nucleation factors. A nucleationfactor promotes nucleation of a crystal of the selected cannabinoid. Insome embodiments, the methods of crystallizing cannabinoids describedherein require application of 1, 2, 3, 4, 5, 6, or more nucleationfactors. In some embodiments, the methods of crystallizing cannabinoidsdescribed herein require vacuum. In some embodiments, the methods ofcrystallizing cannabinoids described herein require vacuum and one othernucleation factor applied before the vacuum.

In some embodiments, the nucleation factor is selected from the groupconsisting of introducing a i) seed crystal (adding crystal of theselected cannabinoid into the solution containing a substantiallydissolved selected cannabinoid), ii) vacuum (exposing the solutioncontaining a substantially dissolved selected cannabinoid into a vacuum,usually applied as final nucleation factor), iii) agitation (e.g.,mechanically agitating the solution containing a substantially dissolvedselected cannabinoid), iv) moisture (increasing or maintaining themoisture content of the solution containing a substantially dissolvedselected cannabinoid), v) aeration (aerating the solution containing asubstantially dissolved selected cannabinoid), and combinations thereof.In some embodiments, the nucleation factor is selected from the groupconsisting of i) seed crystal (introducing a crystal of the selectedcannabinoid into the solution containing a substantially dissolvedselected cannabinoid), ii) vacuum (exposing the solution containing asubstantially dissolved selected cannabinoid into a vacuum, usually asfinal nucleation factor), and iii) agitation (mechanically agitating thesolution containing a substantially dissolved selected cannabinoid). Insome embodiments, the nucleation factor is selected from the groupconsisting of increasing or maintaining the moisture content of thesolution containing a substantially dissolved selected cannabinoid,aerating the solution containing a substantially dissolved selectedcannabinoid, and combinations thereof.

In some embodiments, the method of selective crystallization describedherein requires exposure of the solution containing a substantiallydissolved selected cannabinoid to a vacuum.

In some embodiments, the method of selective crystallization describedherein comprises exposing the solution containing a substantiallydissolved selected cannabinoid to a vacuum followed by exposing thesolution to one or more additional nucleation factors selected from thegroup consisting of: cold shock, introducing a crystal of the selectedcannabinoid into the dissolved cannabinoid solution (seed crystal),mechanically agitating the dissolved cannabinoid solution, andcombinations thereof. In some embodiments, the method of selectivecrystallization described herein comprises exposing the solutioncontaining a substantially dissolved selected cannabinoid to one or morenucleation factors selected from the group consisting of: cold shock,introducing a crystal of the selected cannabinoid into the dissolvedcannabinoid solution (seed crystal), mechanically agitating thedissolved cannabinoid solution, and combinations thereof before exposureof the solution to a vacuum.

In some embodiments, the method of selective crystallization requires(i) agitating the solution containing a substantially dissolvedcannabinoid and (ii) exposing the solution containing a substantiallydissolved selected cannabinoid to a vacuum. In some embodiments, step(i) is performed before step (ii). In some embodiments, step (ii) isperformed before step (i). In some embodiments, step (i) and step (ii)are simultaneously performed (e.g., stir bar or sonicator in vacuumchamber).

In some embodiments, the method of selective crystallization comprises:(i) introducing the solution to the nucleation factors, cold shock, (i)mechanical agitation; (iii) introducing a crystal of the selectedcannabinoid into the dissolved cannabinoid solution (seed crystal) and(iv) introducing the solution into a vacuum. In some embodiments, step(i) is performed before steps (ii)-(iv). In some embodiments, step (iii)is performed before step (ii) and step (iv) is done last. FIG. 17B showsthe effect of cold shock and mechanical agitation. In some embodiments,these nucleation factors thicken the cannabinoid solution and result inbubble formation which aids cannabinoid nucleation.

In some embodiments, exposure of the solution containing a substantiallydissolved selected cannabinoid to a nucleation factor increases the rateof crystallization of the selected cannabinoid by about 5% to about 400%compared to the same method that does not expose the solution containinga substantially dissolved selected cannabinoid to a nucleation factor.For example, exposure of the solution containing a substantiallydissolved selected cannabinoid to a nucleation factor increases the rateof crystallization by about 5%, about 10%, about 20%, about 30%, about40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%,about 125%, about 150%, about 175%, about 200%, about 225%, about 250%,about 275%, about 300%, about 325%, about 350%, about 375%, or about400% compared to the same method that does not expose the solutioncontaining a substantially dissolved selected cannabinoid to anucleation factor, including all values and subranges therebetweeninclusive of endpoints. In some embodiments, increased rate ofcrystallization is measured by % of selected cannabinoid that iscrystallized over time (e.g., the percentage of selected cannabinoid byweight or by moles of the solution per time, for example, per minute,per hour, or per day). In some embodiments, the increased rate ofcrystallization is measured by the total % of selected cannabinoid thatcrystallized at a given time, for example, at 5 minutes, at 10 minutes,at 15 minutes, at 20 minutes, at 25 minutes, at 30 minutes, at 35minutes, at 40 minutes, at 45 minutes, at 50 minutes, about 55 minutes,at 1 hour, at 2 hours, at 3 hours, at 4 hours, at 5 hours, at 6 hours,at 7 hours, at 8 hours, at 9 hours, at 10 hours, at 11 hours, at 12hours, at 13 hours, at 14 hours, at 15 hours, at 16 hours, at 17 hours,at 18 hours, at 19 hours, at 20 hours, about 21 hours, about 22 hours,about 23 hours, about 1 day, about 1.5 days, about 2 days, about 3 days,about 4 days, about 5 days, about 6 days, about 7 days, about 1 week,about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 1month. In some embodiments, nucleation factors improve the quality ofcrystallization (e.g. providing more uniform crystal size, and/orsmaller crystal size).

In some embodiments, exposure of the solution containing a substantiallydissolved selected cannabinoid to a vacuum increases the rate ofcrystallization of the selected cannabinoid by about 5% to about 400%compared to the same method that does not expose the solution containinga substantially dissolved selected cannabinoid to a vacuum. For example,exposure of the solution containing a substantially dissolved selectedcannabinoid to a vacuum increases the rate of crystallization by about5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%,about 70%, about 80%, about 90%, about 100%, about 125%, about 150%,about 175%, about 200%, about 225%, about 250%, about 275%, about 300%,about 325%, about 350%, about 375%, or about 400% compared to the samemethod that does not expose the solution containing a substantiallydissolved selected cannabinoid to a vacuum, including all values andsubranges therebetween inclusive of endpoints. In some embodiments,increased rate of crystallization is measured by % of selectedcannabinoid that is crystallized over time (e.g., the percentage ofselected cannabinoid by weight or by moles of the solution per time, forexample, per minute, per hour, or per day). In some embodiments, theincreased rate of crystallization is measured by the total % of selectedcannabinoid that crystallized at a given time, for example, at 5minutes, at 10 minutes, at 15 minutes, at 20 minutes, at 25 minutes, at30 minutes, at 35 minutes, at 40 minutes, at 45 minutes, at 50 minutes,about 55 minutes, at 1 hour, at 2 hours, at 3 hours, at 4 hours, at 5hours, at 6 hours, at 7 hours, at 8 hours, at 9 hours, at 10 hours, at11 hours, at 12 hours, at 13 hours, at 14 hours, at 15 hours, at 16hours, at 17 hours, at 18 hours, at 19 hours, at 20 hours, about 21hours, about 22 hours, about 23 hours, about 1 day, about 1.5 days,about 2 days, about 3 days, about 4 days, about 5 days, about 6 days,about 7 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks,about 5 weeks, or about 1 month. In some embodiments, exposure of thesolution to a vacuum improves the quality of crystallization (e.g.providing more uniform crystal size, and/or smaller crystal size).

In some embodiments, exposure of the solution containing a substantiallydissolved selected cannabinoid to a vacuum and mechanically agitatingthe solution increases the rate of crystallization of the selectedcannabinoid by about 5% to about 400% compared to the same method thatdoes not expose the solution containing a substantially dissolvedselected cannabinoid to a vacuum and mechanically agitate the solution.For example, exposure of the solution containing a substantiallydissolved selected cannabinoid to a vacuum and mechanical agitation ofthe solution increases the rate of crystallization by about 5%, about10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%,about 80%, about 90%, about 100%, about 125%, about 150%, about 175%,about 200%, about 225%, about 250%, about 275%, about 300%, about 325%,about 350%, about 375%, or about 400% compared to the same method thatdoes not expose the solution containing a substantially dissolvedselected cannabinoid to a vacuum and does not mechanically agitate thesolution, including all values and subranges therebetween inclusive ofendpoints. In some embodiments, increased rate of crystallization ismeasured by % of selected cannabinoid that is crystallized over time,(e.g., the percentage of selected cannabinoid by weight or by moles ofthe solution per time, for example, per minute, per hour, or per day).In some embodiments, the increased rate of crystallization is measuredby the total % of selected cannabinoid that crystallized at a giventime, for example, at 5 minutes, at 10 minutes, at 15 minutes, at 20minutes, at 25 minutes, at 30 minutes, at 35 minutes, at 40 minutes, at45 minutes, at 50 minutes, about 55 minutes, at 1 hour, at 2 hours, at 3hours, at 4 hours, at 5 hours, at 6 hours, at 7 hours, at 8 hours, at 9hours, at 10 hours, at 11 hours, at 12 hours, at 13 hours, at 14 hours,at 15 hours, at 16 hours, at 17 hours, at 18 hours, at 19 hours, at 20hours, about 21 hours, about 22 hours, about 23 hours, about 1 day,about 1.5 days, about 2 days, about 3 days, about 4 days, about 5 days,about 6 days, about 7 days, about 1 week, about 2 weeks, about 3 weeks,about 4 weeks, about 5 weeks, or about 1 month. In some embodiments,exposure of the solution to a vacuum and mechanical agitation of thesolution improves the quality of crystallization (e.g. providing moreuniform crystal size, and/or smaller crystal size).

In some embodiments, exposure of the solution containing a substantiallydissolved selected cannabinoid to a nucleation factor reduces the lengthof time required to crystallize 95% of the selected cannabinoid from thesolution comprising a plurality of cannabinoids. In some embodiments,exposure of the solution containing a substantially dissolved selectedcannabinoid to a nucleation factor reduces the time required tocrystallize 95% of the selected cannabinoid by about 10%, about 20%,about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, orabout 90%, including all ranges and subranges therebetween, as comparedto a solution containing a substantially dissolved selected cannabinoidthat is not exposed to a nucleation factor.

The following paragraphs describe the aforementioned nucleation factorsin more detail:

Nucleation Factor—Seed Crystal

In some embodiments, the nucleation factor comprises introducing acrystal of the selected cannabinoid into the solution containing asubstantially dissolved selected cannabinoid, also referred to as a“seed crystal”. For example, a CBD crystal may be added to a solution inwhich CBD is the selected cannabinoid. In some embodiments, the rate ofcrystallization of a selected cannabinoid from a solution containing asubstantially dissolved selected cannabinoid comprising a seed crystalis higher than the rate of crystallization of the selected cannabinoidfrom a solution containing a substantially dissolved selectedcannabinoid that does not contain a seed crystal. In some embodiments,the rate of crystallization of a selected cannabinoid from a solutioncontaining a substantially dissolved selected cannabinoid comprising aseed crystal is about 5% to about 400% higher than the rate ofcrystallization of the selected cannabinoid from solution containing asubstantially dissolved selected cannabinoid that does not contain aseed crystal. For example, the rate of crystallization of a selectedcannabinoid from a solution containing a substantially dissolvedselected cannabinoid comprising a seed crystal is about 5%, about 10%,about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about80%, about 90%, about 100%, about 125%, about 150%, about 175%, about200%, about 225%, about 250%, about 275%, about 300%, about 325%, about350%, about 375%, or about 400% higher than the rate of crystallizationof the selected cannabinoid from solution containing a substantiallydissolved selected cannabinoid that does not contain a seed crystal,including all values and subranges therebetween, inclusive of endpoints.

Nucleation Factor—Mechanical Agitation

In some embodiments, the nucleation factor is mechanical agitation ofthe solution containing a substantially dissolved selected cannabinoid.Mechanical agitation may comprise any one of vibrating, shaking,stirring, sonicating, or mixing the solution. Without wishing to bebound by any one theory, the instant inventors believe that themechanical agitation cavitates the solution, creating nucleation sites.

Nucleation Factor—Moisture Content

In some embodiments, the nucleation factor is increasing or maintainingthe moisture content of the solution containing a substantiallydissolved selected cannabinoid. In some embodiments, moisture isintroduced to the solution containing a substantially dissolved selectedcannabinoid. In some embodiments, moisture is introduced to the solutioncontaining a substantially dissolved selected cannabinoid via a vacuumoven. In some embodiments, the nucleation factor is increasing ormaintaining the humidity of the solution containing a substantiallydissolved selected cannabinoid. In some embodiments, humidity isintroduced to the solution containing a substantially dissolved selectedcannabinoid. In some embodiments, humidity is introduced to the solutioncontaining a substantially dissolved selected cannabinoid via a vacuumoven.

Nucleation Factor—Vacuum

In some embodiments, the nucleation factor is the introduction of thesolution containing a substantially dissolved selected cannabinoid to avacuum. In some embodiments, the pressure of the vacuum is between about−0.1 atm and about 0.25 atm. For example, the pressure of the vacuum isbelow about −0.1 atm, about −0.09 atm, about −0.08 atm, about −0.07 atm,about −0.06 atm, about −0.05 atm, about −0.04 atm, about −0.03 atm,about −0.02 atm, about −0.01 atm, 0 atm, about 0.01 atm, about 0.02 atm,about 0.03 atm, about 0.04 atm, about 0.05 atm, about 0.06 atm, about0.07 atm, about 0.08 atm, about 0.09 atm, about 0.1 atm, about 0.15 atm,about 0.2 atm, or about 0.25 atm, including all subranges and valuestherebetween, inclusive of endpoints. In some embodiments, the pressureof the vacuum is between about 0.03 atm and about 0.06 atm. In someembodiments, the pressure of the vacuum is between about −0.03 atm andabout −0.06 atm. In some embodiments, the pressure of the vacuum is lessthan about 1 μmHg. In some embodiments, the pressure of the vacuum isbetween about −45 inHg and −5 inHg, for example, below about −45 inHg,about −40 inHg, about −35 inHg, about −30 inHg, about −25 inHg, about−20 inHg, about −15 inHg, about −10 inHg, or about −5 inHg. Unlessotherwise stated or impossible unless below sea level, the pressuresdescribed herein are measured at an altitude of 5,280 feet.

In some embodiments, the vacuum nucleation factor is exposing thesolution to less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%,13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%,27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%,41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%,55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%,69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%,83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% of sea level atmosphericpressure, including all ranges and subranges therebetween. In someembodiments, the vacuum nucleation factor is exposing the solution to atleast 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%,16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%,30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%,44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%,58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%,72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%,86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%vacuum, including all ranges and subranges therebetween. In someembodiments, the vacuum is a vacuum oven. In some embodiments, thetemperature of the vacuum oven is between 25° C. and about 125° C. Forexample, the temperature of the vacuum oven is about 25° C., about 30°C., about 35° C., about 40° C., about 45° C., about 50° C., about 55°C., about 60° C., about 65° C., about 70° C., about 75° C., about 80°C., about 85° C., about 90° C., about 90° C., about 95° C., about 100°C., about 105° C., about 110° C., about 115° C., about 120° C., or about125° C., including all values and subranges therebetween inclusive ofendpoints. In some embodiments, the temperature of the vacuum oven isabout 33° C. In some embodiments, the temperature of the vacuum oven isabout 34° C. In some embodiments, the temperature of the vacuum oven isabout 35° C.

Nucleation Factor—Aeration

In some embodiments, the nucleation factor is aerating the solutioncontaining a substantially dissolved selected cannabinoid. In someembodiments, aerating the solution containing a substantially dissolvedselected cannabinoid comprises introducing a gas to the cooled solution.In some embodiments, carbon dioxide is introduced to the solutioncontaining a substantially dissolved selected cannabinoid. Personshaving skill in the art will be familiar with various techniques anddevices for aerating solutions, including air flow below the surface ofa liquid (e.g., via a tube or aeration stone).

Nucleation Factor—Cold Shock

In some embodiments, the nucleation factor comprises decreasing thetemperature of the solution containing a substantially dissolvedselected cannabinoid to about −5° C. or lower (referred to herein as“cold shock”). In some embodiments, cold shock comprises decreasing thetemperature of the solution containing a substantially dissolvedselected cannabinoid to a temperature between about −5° C. and about−20° C. For example, the temperature of the solution may be decreased toabout −5° C., about −6° C., about −7° C., about −8° C., about −9° C.,about −10° C., about −11° C., about −12° C., about −13° C., about −14°C., about −15° C., about −16° C., about −17° C., about −18° C., about−19° C., or about −20° C., including all values and subrangestherebetween. In some embodiments, cold shock comprises decreasing thetemperature of the solution to about −20° C.

In some embodiments, cold shock comprises reducing the temperature ofthe solution as quickly as possible. In some embodiments, cold shockonly requires achieving a desired temperature, without regard to thespeed of the temperature change. That is, in some embodiments, the coldshock treatment thickens the cannabinoid solution, thereby increasingthe effectiveness of the agitation and or vacuum step. Thus, in someembodiments, the rate of cooling is only a matter of convenience.

In some embodiments, the temperature of the solution is decreased byabout 1° C. every minute, every 5 minutes, every 10 minutes, every 15minutes, every 20 minutes, every 30 minutes, or every hour. In someembodiments, the temperature of the solution is decreased by about 5° C.every minute, every 5 minutes, every 10 minutes, every 15 minutes, every20 minutes, every 30 minutes, or every hour. In some embodiments, thetemperature of the solution is decreased by about 10° C. every minute,every 5 minutes, every 10 minutes, every 15 minutes, every 20 minutes,every 30 minutes, or every hour. In some embodiments, the temperature ofthe solution is decreased by about 15° C. every minute, every 5 minutes,every 10 minutes, every 15 minutes, every 20 minutes, every 30 minutes,or every hour. In some embodiments, the temperature of the solution isdecreased by about 20° C. every minute, every 5 minutes, every 10minutes, every 15 minutes, every 20 minutes, every 30 minutes, or everyhour. In some embodiments, the temperature of the solution is decreasedby about 30° C. every minute, every 5 minutes, every 10 minutes, every15 minutes, every 20 minutes, every 30 minutes, or every hour. In someembodiments, the temperature of the solution is decreased by about 40°C. every minute, every 5 minutes, every 10 minutes, every 15 minutes,every 20 minutes, every 30 minutes, or every hour. In some embodiments,the temperature of the solution is decreased by about 50° C. everyminute, every 5 minutes, every 10 minutes, every 15 minutes, every 20minutes, every 30 minutes, or every hour.

In some embodiments, the temperature of the solution containing thesubstantially dissolved cannabinoid is decreased to from about −5° C.and about −20° C. within about 2 hours. In some embodiments, thetemperature is decreased to from about −5° C. and about −20° C. withinabout 15 minutes. In some embodiments, the solution containing thesubstantially dissolved selected cannabinoid is cold shocked and held ata temperature from about −5° C. to about −20° C. for from about 5minutes to about 24 hours. For example, the temperature of the solutioncontaining the substantially dissolved selected cannabinoid may be heldat a temperature of about −5° C., about −6° C., about −7° C., about −8°C., about −9° C., about −10° C., about −11° C., about −12° C., about−13° C., about −14° C., about −15° C., about −16° C., about −17° C.,about −18° C., about −19° C., or about −20° C., including all values andranges therebetween, inclusive of endpoints, for about 5 minutes, about10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about50 minutes, about 55 minutes, about 60 minutes, about 1.5 hours, about 2hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours,about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5hours, about 9 hours, about 9.5 hours, about 10 hours, about 10.5 hours,about 11 hours, about 11.5 hours, about 12 hours, about 12.5 hours,about 13 hours, about 13.5 hours, about 14 hours, about 14.5 hours,about 15 hours, about 15.5 hours, about 16 hours, about 16.5 hours,about 17 hours, about 17.5 hours, about 18 hours, about 18.5 hours,about 19 hours, about 19.5 hours, about 20 hours, about 20.5 hours,about 21 hours, about 21.5 hours, about 22 hours, about 22.5 hours,about 23 hours, about 23.5 hours, or about 24 hours, including allvalues and ranges therebetween, inclusive of endpoints. In embodiments,the temperature is held at about −20° C. for about 15 minutes.

Crystals of the Selected Cannabinoid

In some embodiments, the method separates cannabinoids by selectivelycrystalizing the selected cannabinoid. In some embodiments, thenucleation factors of the present disclosure trigger controlledcrystallization that selectively crystallizes the selected cannabinoidwhile reducing the amount of contaminants in the lattice structure. Insome embodiments, the crystals of the selected cannabinoid are betweenabout 2 μm and about 5 μm in size, for example, about 2 μm, about 2.5μm, about 3 μm, about 3.5 μm, about 4 μm, about 4.5 μm, or about 5 μm.In some embodiments, the crystals of the selected cannabinoid aregreater than 2 μm in size, for example, about 2 μm, about 2.5 μm, about3 μm, about 3.5 μm, about 4 μm, about 4.5 μm, about 5 μm, about 6 μm,about 7 μm, about 8 μm, about 9 μm, about 10 μm, about 11 μm, about 12μm, about 13 μm, about 14 μm, about 15 μm, about 16 μm, about 17 μm,about 18 μm, about 19 μm, about 20 μm, about 21 μm, about 22 μm, about23 μm, about 24 μm, about 25 μm, about 26 μm, about 27 μm, about 28 μm,about 29 μm, about 30 μm, or greater. As used herein, the term “size”may refer to a largest crystal's diameter or length. In someembodiments, the crystals of the selected cannabinoid are greater thanor equal to about 5 μm, about 10 μm, about 15 μm, about 20 μm, about 25μm, or about 30 μm in size. In some embodiments, the crystals of theselected cannabinoid are greater than or equal to about 25 μm in size,for example, 25 μm, about 26 μm, about 27 μm, about 28 μm, about 29 μm,about 30 μm, about 31 μm, about 32 μm, about 33 μm, about 34 μm, about35 μm, or more. Thus, a rod-shaped crystal would have a particle sizeroughly equivalent to the length of the crystal. Crystal size may bemeasured using any one of the following techniques: x-ray scattering,small angle x-ray scattering, wide angle x-ray scattering, dynamic lightscattering, analytical ultracentrifugation, size exclusionchromatography, and photon correlation spectroscopy.

In some embodiments, the method provides crystals of the selectedcannabinoid that are at least 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm,9 μm, 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 17 μm, 18 μm, 19μm, 20 μm, 21 μm, 22 μm, 23 μm, 24 μm, 25 μm, 26 μm, 27 μm, 28 μm, 29μm, 30 μm, 31 μm, 32 μm, 33 μm, 34 μm, 35 μm, 36 μm, 37 μm, 38 μm, 39μm, 40 μm, 41 μm, 42 μm, 43 μm, 44 μm, 45 μm, 46 μm, 47 μm, 48 μm, 49μm, 50 μm, 51 μm, 52 μm, 53 μm, 54 μm, 55 μm, 56 μm, 57 μm, 58 μm, 59μm, 60 μm, 61 μm, 62 μm, 63 μm, 64 μm, 65 μm, 66 μm, 67 μm, 68 μm, 69μm, 70 μm, 71 μm, 72 μm, 73 μm, 74 μm, 75 μm, 76 μm, 77 μm, 78 μm, 79μm, 80 μm, or 81 μm in size, including all ranges and subrangestherebetween. In some embodiments, the average crystal size of theselected cannabinoid are at least 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8μm, 9 μm, 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 17 μm, 18 μm,19 μm, 20 μm, 21 μm, 22 μm, 23 μm, 24 μm, 25 μm, 26 μm, 27 μm, 28 μm, 29μm, 30 μm, 31 μm, 32 μm, 33 μm, 34 μm, 35 μm, 36 μm, 37 μm, 38 μm, 39μm, 40 μm, 41 μm, 42 μm, 43 μm, 44 μm, 45 μm, 46 μm, 47 μm, 48 μm, 49μm, 50 μm, 51 μm, 52 μm, 53 μm, 54 μm, 55 μm, 56 μm, 57 μm, 58 μm, 59μm, 60 μm, 61 μm, 62 μm, 63 μm, 64 μm, 65 μm, 66 μm, 67 μm, 68 μm, 69μm, 70 μm, 71 μm, 72 μm, 73 μm, 74 μm, 75 μm, 76 μm, 77 μm, 78 μm, 79μm, 80 μm, or 81 μm in size, including all ranges and subrangestherebetween. In some embodiments, the method provides crystals of theselected cannabinoid that are greater than or equal to about 5 μm, about10 μm, about 15 μm, about 20 μm, about 25 μm, or about 30 μm in size. Insome embodiments, the method provides crystals of the selectedcannabinoid that are greater than or equal to about 25 μm in size, forexample, 25 μm, about 26 μm, about 27 μm, about 28 μm, about 29 μm,about 30 μm, about 31 μm, about 32 μm, about 33 μm, about 34 μm, about35 μm, or more. In some embodiments, the method provides crystals thatare less than about 100 μm, less than about 110 μm, less than about 120μm, less than about 130 μm, less than about 140 μm, or less than about150 μm. In some embodiments, the method provides crystals between about2 μm and 150 μm, 2 μm and 140 μm, 2 μm and 130 μm, 2 μm and 120 μm, 2 μmand 110 μm, 2 μm and 100 μm, 10 μm and 150 μm, 10 μm and 140 μm, 10 μmand 130 μm, 10 μm and 120 μm, 2 μm and 110 μm, 10 μm and 100 μm, 20 μmand 150 μm, 20 μm and 140 μm, 20 μm and 130 μm, 20 μm and 120 μm, 20 μmand 110 μm, or 20 μm and 100 μm in size.

In some embodiments, at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,93%, 94%, or 95% of the cannabinoid in a cannabinoid solution forms intocrystals of at least 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, 10μm, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 17 μm, 18 μm, 19 μm, 20μm, 21 μm, 22 μm, 23 μm, 24 μm, 25 μm, 26 μm, 27 μm, 28 μm, 29 μm, 30μm, 31 μm, 32 μm, 33 μm, 34 μm, 35 μm, 36 μm, 37 μm, 38 μm, 39 μm, 40μm, 41 μm, 42 μm, 43 μm, 44 μm, 45 μm, 46 μm, 47 μm, 48 μm, 49 μm, 50μm, 51 μm, 52 μm, 53 μm, 54 μm, 55 μm, 56 μm, 57 μm, 58 μm, 59 μm, 60μm, 61 μm, 62 μm, 63 μm, 64 μm, 65 μm, 66 μm, 67 μm, 68 μm, 69 μm, 70μm, 71 μm, 72 μm, 73 μm, 74 μm, 75 μm, 76 μm, 77 μm, 78 μm, 79 μm, 80μm, or 81 μm in size, including all ranges and subranges therebetween.

In some embodiments, the method provides crystals of the selectedcannabinoid that are substantially homogenous in size. The term“substantially homogenous in size” means that greater than 70%, greaterthan 75%, greater than 80%, greater than 85%, greater than 90%, greaterthan 95%, greater than 96%, greater than 97%, greater than 98%, greaterthan 99%, or 100% of the crystals of the selected cannabinoid exhibit asize that is within about plus or minus 20%, 30%, 40%, 50%, 75%, or 100%of the mean crystal size.

In some embodiments, at least 90%, for example, at least 91%, at least92%, at least 93%, at least 94%, at least 95%, at least 96%, at least97%, at least 98%, at least 99%, or 100% of the selected cannabinoid iscrystallized from the solution containing a substantially dissolvedcannabinoid. In some embodiments, at least 95%, for example, at least95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% ofthe selected cannabinoid is crystallized from the solution containing asubstantially dissolved cannabinoid.

In some embodiments, at least 90%, for example, at least 91%, at least92%, at least 93%, at least 94%, at least 95%, at least 96%, at least97%, at least 98%, at least 99%, or 100% of the selected cannabinoid iscrystallized from the solution containing a substantially dissolvedcannabinoid, within about 1 hour to about 24 hours, within about 4 hoursto about 10 hours, within about 10 hours to about 16 hours, or withinabout 16 to about 24 hours, including all values and ranges in between,including about 1 hour, about 2 hours, about 3 hours, about 4 hours,about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours,about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours,about 23 hours, or about 24 hours. In some embodiments, greater than orequal to about 95% of the selected cannabinoid is crystallized out ofsolution within about 10 hours.

IIIB. Method of Purifying a Selected Cannabinoid from a Mixture ofCannabinoids

In some embodiments, provided herein is a method of purifying a selectedcannabinoid from a mixture of cannabinoids, said method comprising: (a)providing a mixture of cannabinoids comprising a crystallizedcannabinoid, wherein the crystallized cannabinoid comprises crystalsthat are at least about 25 μm in size; (b) forcing the mixture ofcannabinoids through a filter, said filter having a pore size smallerthan about 2 μm or smaller than about 25 μm; wherein this step isperformed at a temperature below the melting point of the crystallizedcannabinoid, wherein the crystallized cannabinoid remains on the filter;and (c) collecting the crystallized cannabinoid from the filter, therebypurifying the selected cannabinoid. In some embodiments, the selectedcannabinoid is selected from the group consisting of CBN, CBD, THC,THCV, CBDA, CBDV, THCA, CBG, CBGA, CBNA, CBDVA, CBCA, and CBC. In someembodiments, the method comprises purifying a selected cannabinoid fromnon-specific lipid-soluble material. In some embodiments, the methodcomprises purifying a selected cannabinoid from one or more othercannabinoids.

Providing a Mixture Comprising a Crystallized Cannabinoid

In some embodiments, the method comprises providing a mixture comprisinga crystallized cannabinoid. In some embodiments, the method comprisesproviding a mixture of cannabinoids comprising a crystallizedcannabinoid. In some embodiments, the crystallized cannabinoid comprisescrystals that are at least about 2 μm in size, for example, at leastabout 2 μm, at least about 3 μm, at least about 4 μm, at least about 5μm, at least about 6 μm, at least about 7 μm, at least about 8 μm, atleast about 9 μm, at least about 10 μm, at least about 11 μm, at leastabout 12 μm, at least about 13 μm, at least about 14 μm, at least about15 μm, at least about 16 μm, at least about 17 μm, at least about 18 μm,at least about 19 μm, or at least about 20 μm in size. In someembodiments, the crystallized cannabinoid comprises crystals that arebetween about 2 μm and 5 μm in size, for example, about 2 μm, about 2.5μm, about 3 μm, about 3.5 μm, about 4 μm, about 4.5 μm, or about 5 μm insize. In some embodiments, the crystals of the selected cannabinoid aregreater than or equal to about 5 μm, about 10 μm, about 15 μm, about 20μm, about 25 μm, or about 30 μm in size. In some embodiments, thecrystals of the selected cannabinoid are greater than or equal to about25 μm in size, for example, about 25 μm, about 26 μm, about 27 μm, about28 μm, about 29 μm, about 30 μm, about 31 μm, about 32 μm, about 33 μm,about 34 μm, about 35 μm, or more. In some embodiments, at least 85%,86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, or 95% of the cannabinoidin a cannabinoid solution forms into crystals of at least 2 μm, 3 μm, 4μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, 15μm, 16 μm, 17 μm, 18 μm, 19 μm, 20 μm, 21 μm, 22 μm, 23 μm, 24 μm, 25μm, 26 μm, 27 μm, 28 μm, 29 μm, 30 μm, 31 μm, 32 μm, 33 μm, 34 μm, 35μm, 36 μm, 37 μm, 38 μm, 39 μm, 40 μm, 41 μm, 42 μm, 43 μm, 44 μm, 45μm, 46 μm, 47 μm, 48 μm, 49 μm, 50 μm, 51 μm, 52 μm, 53 μm, 54 μm, 55μm, 56 μm, 57 μm, 58 μm, 59 μm, 60 μm, 61 μm, 62 μm, 63 μm, 64 μm, 65μm, 66 μm, 67 μm, 68 μm, 69 μm, 70 μm, 71 μm, 72 μm, 73 μm, 74 μm, 75μm, 76 μm, 77 μm, 78 μm, 79 μm, 80 μm, or 81 μm in size, including allranges and subranges therebetween.

In some embodiments, the mixture comprising a crystallized cannabinoidis produced using the methods of Section IIIA In some embodiments, themixture is a mixture of two or more cannabinoids. In some embodiments,the mixture comprising a crystallized cannabinoid contains a singlecannabinoid present in both a crystallized and dissolved state.

In some embodiments, a mixture comprising a crystallized cannabinoid isproduced by allowing Cannabis oil to age for at least one week, at leasttwo weeks, at least three weeks, at least four weeks, at least fiveweeks, at least 1 month, at least 2 months, at least 3 months, at least4 months, at least 5 months, at least 6 months, at least 7 months, atleast 8 months, at least 9 months, at least 10 months, at least 11months, or at least 12 months.

In some embodiments, a mixture comprising a crystallized cannabinoidcomprises non-specific lipid-soluble material or “ballast” e.g. waxes,wax esters and glycerides, unsaturated fatty acid residues, terpenes,carotenes, chlorophyll, flavonoids, pigments, sugars, cellulosecompounds, and minerals. In some embodiments, a mixture comprising acrystallized cannabinoid comprises one or more additional cannabinoids.Examples of cannabinoids are provided throughout this disclosure.

Forcing the Mixture Through a Filter

In some embodiments, the method comprises forcing a mixture comprising acrystallized cannabinoid through a filter, said filter having a poresize smaller than about 2 μm or smaller than about 25 μm; wherein thisstep is performed at a temperature below the melting point of thecrystallized cannabinoid, and wherein the crystallized cannabinoidremains on the filter. In some embodiments, the mixture is a mixture ofcannabinoids.

In some embodiments, the method comprises forcing a mixture comprising acrystallized cannabinoid through a filter, said filter having a poresize smaller than about 2 μm or smaller than about 25 μm; wherein thisstep is performed at a temperature below the melting point of thecrystallized cannabinoid, and wherein the crystallized cannabinoidremains on the filter.

In some embodiments, the filtration step is conducted between about 0.1°C. and about 20° C. below the melting point of the crystallizedcannabinoid, for example, at least about 0.1° C., about 0.2° C., about0.3° C., about 0.4° C., about 0.5° C., about 0.6° C., about 0.7° C.,about 0.8° C., about 0.9° C., about 1° C., about 2° C., about 3° C.,about 4° C., about 5° C., about 6° C., about 7° C., about 8° C., about9° C., about 10° C., about 11° C., about 12° C., about 13° C., about 14°C., about 15° C., about 16° C., about 17° C., about 18° C., about 19°C., or about 20° C. below the melting point of the crystallizedcannabinoid, including all values and ranges there between, inclusive ofendpoints. In some embodiments, the filtration step is conducted betweenabout 0.5° C. and 10° C. below the melting point of the crystallizedcannabinoid.

In some embodiments, the method comprises forcing the mixture comprisinga crystallized cannabinoid through a filter having a pore size smallerthan 70%, 80%, 90%, or 95% of the crystallized cannabinoid. Thus, insome embodiments, the method comprises forcing the mixture comprising acrystallized cannabinoid through a filter having a pore size smallerthan about 25 μm, for example, smaller than about 25 μm, smaller thanabout 24 μm, smaller than about 23 μm, smaller than about 22 μm, smallerthan about 21 μm, smaller than about 20 μm, smaller than about 19 μm,smaller than about 18 μm, smaller than about 17 μm, smaller than about16 μm, smaller than about 15 μm, smaller than about 14 μm, smaller thanabout 13 μm, smaller than about 12 μm, smaller than about 11 μm, smallerthan about 10 μm, smaller than about 9 μm, smaller than about 8 μm,smaller than about 7 μm, smaller than about 6 μm, smaller than about 5μm, smaller than about 4 μm, smaller than about 3 μm, smaller than about2 μm, smaller than about 1.9 μm, smaller than about 1.8 μm, smaller thanabout 1.7 μm, smaller than about 1.6 μm, smaller than about 1.5 μm,smaller than about 1.4 μm, smaller than about 1.3 μm, smaller than about1.2 μm, smaller than about 1.1 μm, smaller than about 1.0 μm, smallerthan about 0.9 μm, smaller than about 0.8 μm, smaller than about 0.7 μm,smaller than about 0.6 μm, smaller than about 0.5 μm, smaller than about0.4 μm, smaller than about 0.3 μm, smaller than about 0.2 μm, or smallerthan about 0.1 μm. In some embodiments, the filter compriseshydrophilized poly(vinylildene difluoride) (PVDF), polyetheresulfone(PES), cellulose phosphate, diethylaminoethyl cellulose, polysufone,regenerated cellulose, nylon, cellulose nitrate, cellulose acetate,paper, pegylated PES, modified polyethersulfone, and sulfonated PES, ormodified derivatives thereof.

In some embodiments, the method comprises forcing the mixture throughthe filter via centrifugation, application of force, (e.g. gravity,centripetal, pressure, or vacuum).

In some embodiments, the method comprises forcing the mixture comprisinga crystallized cannabinoid through the filter via centrifugation. Insome embodiments, the mixture is centrifuged at a speed between about1000 rpm and about 20,000 rpm, for example, at least about 1000 rpm,about 2000 rpm, about 3000 rpm, about 4000 rpm, about 5000 rpm, about6000 rpm, about 7000 rpm, about 8000 rpm, about 9000 rpm, about 10,000rpm, about 11000 rpm, about 12000 rpm, about 13,000 rpm, about 14,000rpm, about 15,000 rpm, about 16,000 rpm, about 17,000 rpm, about 18,000rpm, about 19,000 rpm, and about 20,000 rpm, including all ranges andsubranges therebetween. In some embodiments, the mixture of cannabinoidsis centrifuged at a speed between about 1000 rpm and about 7500 rpm. Insome embodiments, the mixture of cannabinoids is centrifuged at a speedbetween about 7500 rpm and about 20,000 rpm. In some embodiments, themixture comprising a crystallized cannabinoid is centrifuged at a speedgreater than or equal to about 20,000 rpm. In some embodiments, themixture comprising a crystallized cannabinoid is centrifuged at a speedbetween about 1000 rpm and about 20,000 rpm for about 30 minutes, about45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5hours, about 3 hours, about 3.5 hours, about 4 hours, or more.

In some embodiments, the method comprises forcing the mixture comprisinga crystallized cannabinoid through the filter via centrifugation, andincreasing temperature of the mixture during centrifugation. In someembodiments, the present disclosure teaches increasing the temperature,to a point below the melting temperature of the crystallizedcannabinoid. Without wishing to be bound by any one theory, theinventors believe that increasing the temperature allows non-cannabinoidcomponents to melt/soften and be pulled through the filter, thusremoving impurities from the crystallized cannabinoid.

In some embodiments, the temperature of the mixture is increased tobetween about 20° C. and about 60° C., for example, about 20° C., about21° C., about 22° C., about 23° C., about 24° C., about 25° C., about26° C., about 27° C., about 28° C., about 29° C., about 30° C., about31° C., about 32° C., about 33° C., about 34° C., about 35° C., about36° C., about 37° C., about 38° C., about 39° C., about 40° C., about41° C., about 42° C., about 43° C., about 44° C., about 45° C., about46° C., about 47° C., about 48° C., about 49° C., about 50° C., about51° C., about 52° C., about 53° C., about 54° C., about 55° C., about56° C., about 57° C., about 58° C., about 59° C., or about 60° C.,including all values and ranges therebetween, inclusive of endpoints. Insome embodiments, the temperature of the mixture is increased to about40° C. during centrifugation. In some embodiments, after centrifugation,the mixture is cooled (e.g., allowed to naturally return) to ambienttemperature (e.g., about 25° C.). In some embodiments, the mixture ofcannabinoids is not cooled to ambient temperature after centrifugation.

In some embodiments, the mixture comprising a crystallized cannabinoidis centrifuged once, and subsequently, the filtrate which containsbyproduct is removed. In some embodiments, the process is repeated oneor more times. For example, the method may comprise (i) subjecting themixture comprising a crystallized cannabinoid to centrifugation; (ii)removing the filtrate containing the byproduct, and repeating steps (i)and (ii). In some embodiments, steps (i) and (ii) are repeated at leastonce, at least twice, at least three times, at least four times, atleast five times, at least six times, at least seven times, at leasteight times, at least nine times, or at least ten times. In someembodiments, the mixture of cannabinoids is centrifuged at about 5000rpm for about 90 minutes twice.

In some embodiments, the method comprises: (i) centrifuging the mixturecomprising a crystallized cannabinoid and increasing the temperatureduring centrifugation; (ii) removing the filtrate and cooling themixture to ambient temperature; (iii) centrifuging the mixture andincreasing the temperature during centrifugation; and (iv) removing thefiltrate and cooling the mixture to ambient temperature. In someembodiments filtering the mixture comprising a crystallized cannabinoidvia centrifuge, with increased temperature (below the melting point ofthe crystal) results in a highly pure cannabinoid product.

In some embodiments, the method comprises: (i) centrifuging the mixturecomprising a crystallized cannabinoid and increasing the temperatureduring centrifugation; (ii) removing the filtrate; (iii) centrifugingthe mixture and increasing the temperature during centrifugation; and(iv) removing the filtrate.

In some embodiments, the method comprises: (i) centrifuging the mixturecomprising a crystallized cannabinoid at a speed of at least about 3000rpm (e.g., about 3000 rpm) for at least about 30 minutes and increasingthe temperature to at least about 40° C. during centrifugation; (ii)removing the filtrate and cooling the mixture to ambient temperature;and repeating (i) and (ii) at least one time. In some embodiments,during step (i) or in the repeat of step (i), the temperature of themixture increases to above 40° C., for example, a temperature of about41° C., about 42° C., about 43° C., about 44° C., about 45° C., about46° C., about 47° C., about 48° C., about 49° C., about 50° C., about51° C., about 52° C., about 53° C., about 54° C., about 55° C., about56° C., about 57° C., about 58° C., about 59° C., or about 60° C.

In some embodiments, the method comprises forcing the mixture throughthe filter via pressure. In some embodiments, the force is about10-20,000 times the force of gravity (g), for example, about 10 g, about50 g, about 100 g, about 200 g, about 300 g, about 400 g, about 500 g,about 600 g, about 700 g, about 800 g, about 900 g, about 1000 g, about1250 g, about 1500 g, about 1750 g, about 2000 g, about 2250 g, about2500 g, about 2750 g, about 3000 g, about 3250 g, about 3500 g, about3750 g, about 4000 g, about 4250 g, about 4500 g, about 4750 g, about5000 g, about 5250 g, about 5500 g, about 5750 g, about 6000 g, about6250 g, about 6500 g, about 6750 g, about 7000 g, about 7250 g, about7500 g, about 7750 g, about 8000 g, about 8250 g, about 8500 g, about8750 g, about 9000 g, about 9250 g, about 9500 g, about 9750 g, about10,000 g, about 10,250 g, about 10,500 g, about 10,750 g, about 11,000g, about 11,250 g, about 11,500 g, about 11,750 g, about 12,000 g, about12,250 g, about 12,500 g, about 12,750 g, about 13,000 g, about 13,250g, about 13,500 g, about 13,750 g, about 14,000 g, about 14,250 g, about14,500 g, about 14,750 g, about 15,000 g, about 15,250 g, about 15,500g, about 15,750 g, about 16,000 g, about 16,250 g, about 16,500 g, about16,750 g, about 17,000 g, about 17,250 g, about 17,500 g, about 17,750g, about 18,000 g, about 18,250 g, about 18,500 g, about 18,750 g, about19,000 g, about 19,250 g, about 19,500 g, about 19,750 g, about 20,000g, or any value or range therebetween, inclusive of endpoints. In someembodiments, the pressure is between about 3 kg/cm² and about 7 kg/cm²,for example, about 3 kg/cm², about 3.5, about 4 kg/cm², about 4.5kg/cm², about 5 kg/cm², about 5.5 kg/cm², about 6 kg/cm², about 6.5kg/cm², about 7 kg/cm², or any value or range therebetween, inclusive ofendpoints. In some embodiments, the pressure is gravity. In someembodiments, the pressure is hydrostatic pressure. In some embodiments,the pressure is air pressure.

In some embodiments, the method comprises forcing the mixture throughthe filter via a vacuum. In some embodiments, the pressure of the vacuumis between about 0.001 atm and about 0.1 atm, for example, about 0.001atm, about 0.005 atm, about 0.01 atm, about 0.02 atm, about 0.03 atm,about 0.04 atm, about 0.05 atm, about 0.06 atm, about 0.07 atm, about0.08 atm, about 0.09 atm, or about 0.1 atm. In some embodiments, thepressure of the vacuum is between about −45 mmHg and −5 mmHg, forexample, about −45 mmHg, about −40 mmHg, about −35 mmHg, about −30 mmHg,about −25 mmHg, about −20 mmHg, about −15 mmHg, about −10 mmHg, or about−5 mmHg. In some embodiments, the pressure of the vacuum is less thanabout 1 micron. In some embodiments, the pressure of the vacuum is lessthan about 1 micron. In some embodiments, the pressure of the vacuum isbetween about −45 inHg and −5 inHg, for example, about −45 inHg, about−40 inHg, about −35 inHg, about −30 inHg, about −25 inHg, about −20inHg, about −15 inHg, about −10 inHg, or about −5 inHg. In someembodiments, the pressure of the vacuum is about −25 mmHg. In someembodiments, the pressure of the vacuum is about −25 inHg.

In some embodiments, after forcing the mixture through the filter,crystals of the selected cannabinoid are retained on the filter.

Collecting the Crystallized Cannabinoid from the Filter

In some embodiments, the crystallized cannabinoid is collected from thefilter, thereby purifying the selected cannabinoid. In some embodiments,the crystallized cannabinoid is selected from the group consisting ofCBN, CBD, THC, THCV, CBDA, CBDV, THCA, CBG, CBGA, CBNA, CBDVA, CBCA, andCBC. In some embodiments, the collected crystallized cannabinoid is atleast 85%, at least 86%, at least 87%, at least 89%, at least 90%, atleast 91%, at least 92%, at least 93%, at least 94%, at least 95%, atleast 96%, at least 97%, at least 98%, or at least 99% pure. In someembodiments, the collected crystallized cannabinoid is at least 98%pure. In some embodiments, the collected crystallized cannabinoidcomprises crystals that are at least about 2 μm in size, for example, atleast about 2 μm, at least about 3 μm, at least about 4 μm, at leastabout 5 μm, at least about 6 μm, at least about 7 μm, at least about 8μm, at least about 9 μm, at least about 10 μm, at least about 11 μm, atleast about 12 μm, at least about 13 μm, at least about 14 μm, at leastabout 15 μm, at least about 16 μm, at least about 17 μm, at least about18 μm, at least about 19 μm, or at least about 20 μm in size. In someembodiments, the collected crystallized cannabinoid comprises crystalsthat are between about 2 μm and 5 μm in size, for example, about 2 μm,about 2.5 μm, about 3 μm, about 3.5 μm, about 4 μm, about 4.5 μm, orabout 5 μm, in size. In some embodiments, the collected crystallizedcannabinoid comprises crystals that are at least about 5 μm, about 10μm, about 15 μm, about 20 μm, about 25 μm, or about 30 μm in size. Insome embodiments, the collected crystallized cannabinoid comprisescrystals that are at least about 25 μm in size, for example, 25 μm,about 26 μm, about 27 μm, about 28 μm, about 29 μm, about 30 μm, about31 μm, about 32 μm, about 33 μm, about 34 μm, about 35 μm, or more.

Optional Additional Purification and Processing Steps

In some embodiments, the crystallized cannabinoid is subjected to one ormore additional purification steps.

In some embodiments, the crystallized cannabinoid is washed with asolvent. In some embodiments, washing occurs in a glass container, forexample, a beaker or a flask. In some embodiments, the solvent is water.In some embodiments, the solvent comprises a salt. Non-limiting examplesof salts include sodium chloride, potassium chloride, ammonium chloride,sodium acetate, sodium citrate, copper sulfate, sodium iodide, ammoniumsulfate, and sodium sulfate.

In some embodiments, the solvent comprises a buffer. The buffer may bean inorganic or an organic buffer. Non-limiting examples of buffersinclude phosphate buffered saline (PBS), phosphate, succinate, citrate,borate, maleate, cacodylate, N-(2-Acetamido)iminodiacetic acid (ADA),2-(N-morpholino)-ethanesulfonic acid (MES),N-(2-acetamido)-2-aminoethanesulfonic acid (ACES),piperazine-N,N′-2-ethanesulfonic acid (PIPES),2-(N-morpholino)-2-hydroxypropanesulfonic acid (MOPSO),N,N-bis-(hydroxyethyl)-2-aminoethanesulfonic acid (BES),3-(N-morpholino)-propanesulfonic acid (MOPS),N-tris-(hydroxymethyl)-2-ethanesulfonic acid (TES),N-2-hydroxyethyl-piperazine-N-2-ethanesulfonic acid (HEPES),3-(N-tris-(hydroxymethyl) methylamino)-2-hydroxypropanesulfonic acid(TAPSO), 3-(N,N-Bis[2-hydroxyethyl]amino)-2-hydroxypropanesulfonic acid(DIPSO), N-(2-Hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonic acid)(HEPPSO), 4-(2-Hydroxyethyl)-1-piperazinepropanesulfonic acid (EPPS),N-[Tris(hydroxymethyl)methyl]glycine (Tricine),N,N-Bis(2-hydroxyethyl)glycine (Bicine),(2-Hydroxy-1,1-bis(hydroxymethyl)ethyl)amino]-1-propanesulfonic acid(TAPS), N-(1,1-Dimethyl-2-hydroxyethyl)-3-amino-2-hydroxypropanesulfonic acid (AA/IPSO), tris (hydroxymethyl) amino-methane (Tris), TRIS-Acetate-EDTA (TAE), glycine,bis[2-hydroxyethyl]iminotris[hydroxymethyl]methane (BisTris), orcombinations thereof.

In some embodiments, the concentration of a buffer and/or salt isbetween about 0.1 mM and 1 M, for example, between about 10 mM to about1 M, between about 20 mM and about 500 mM, between about 50 mM and about300 mM, between about 0.1 mM and about 50 mM, or between about 0.5 mMand about 20 mM. In some embodiments, the concentration of the bufferand/or salt is about 0.1 mM, about 0.2 mM, about 0.3 mM, about 0.4 mM,about 0.5 mM, about 0.6 mM, about 0.7 mM, about 0.8 mM, about 0.9 mM,about 1 mM, about 10 mM, about 20 mM, about 30 mM, about 40 mM, about 50mM, about 60 mM, about 70 mM, about 80 mM, about 90 mM, about 100 mM,about 110 mM, about 120 mM, about 130 mM, about 140 mM, about 150 mM,about 160 mM, about 170 mM, about 180 mM, about 190 mM, about 200 mM,about 210 mM, about 220 mM, about 230 mM, about 240 mM, about 250 mM,about 260 mM, about 270 mM, about 280 mM, about 290 mM, about 300 mM,about 310 mM, about 320 mM, about 330 mM, about 340 mM, about 350 mM,about 360 mM, about 370 mM, about 380 mM, about 390 mM, about 400 mM,about 410 mM, about 420 mM, about 430 mM, about 440 mM, about 450 mM,about 460 mM, about 470 mM, about 480 mM, about 490 mM, about 500 mM,about 510 mM, about 520 mM, about 530 mM, about 540 mM, about 550 mM,about 560 mM, about 570 mM, about 580 mM, about 590 mM, about 600 mM,about 610 mM, about 620 mM, about 630 mM, about 640 mM, about 650 mM,about 660 mM, about 670 mM, about 680 mM, about 690 mM, about 700 mM,about 710 mM, about 720 mM, about 730 mM, about 740 mM, about 750 mM,about 760 mM, about 770 mM, about 780 mM, about 790 mM, about 800 mM,about 810 mM, about 820 mM, about 830 mM, about 840 mM, about 850 mM,about 860 mM, about 870 mM, about 880 mM, about 890 mM, about 900 mM,about 910 mM, about 920 mM, about 930 mM, about 940 mM, about 950 mM,about 960 mM, about 970 mM, about 980 mM, about 990 mM, or about 1 M,including all ranges and subranges therebetween.

In some embodiments, the crystallized cannabinoid is washed with asolvent at a temperature between about 0.1° C. and about 30° C., forexample, about 0.1° C., about 0.2° C., about 0.3° C., about 0.4° C.,about 0.5° C., about 0.6° C., about 0.7° C., about 0.8° C., about 0.9°C., about 1° C., about 2° C., about 3° C., about 4° C., about 5° C.,about 6° C., about 7° C., about 8° C., about 9° C., about 10° C., about11° C., about 12° C., about 13° C., about 14° C., about 15° C., about16° C., about 17° C., about 18° C., about 19° C., about 20° C., about21° C., about 22° C., about 23° C., about 24° C., about 25° C., about26° C., about 27° C., about 28° C., about 29° C., about 30° C., about31° C., about 32° C., about 33° C., about 34° C., about 35° C., about36° C., about 37° C., about 38° C., about 39° C., about 40° C., about41° C., about 42° C., about 43° C., about 44° C., about 45° C., about46° C., about 47° C., about 48° C., about 49° C., about 50° C., about51° C., about 52° C., about 53° C., about 54° C., about 55° C., about56° C., about 57° C., about 58° C., about 59° C., or about 60° C.including all values and ranges therebetween, inclusive of endpoints. Insome embodiments, the crystallized cannabinoid is washed with a solventat a temperature between about 1° C. and about 8° C.

In some embodiments, the pH of the solvent is between about 5.5 andabout 8.5. For example, the pH of the solvent is about 5.5, about 5.6,about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9,about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about7.6, about 7.7, about 7.8, about 7.9, about 8.0, about 8.1, about 8.2,about 8.3, about 8.4, or about 8.5, including all values and rangestherebetween, inclusive of endpoints. In some embodiments, the pH of thesolvent is about 6.5.

In some embodiments, the crystallized cannabinoid is dried. In someembodiments, the crystallized cannabinoid is dried in a vacuum oven, ina desiccator, or using a filtration flask. Suitable temperatures andpressures for the vacuum oven are described throughout this disclosure,for example, in Section IIIA

In some embodiments, the pressure of the vacuum is from about −45 inHgto −5 inHg. For example, the pressure of the vacuum may be stronger thanabout −45 inHg, about −40 inHg, about −35 inHg, about −30 inHg, about−25 inHg, about −20 inHg, about −15 inHg, about −10 inHg, or about −5inHg.

In some embodiments, the temperature of the vacuum oven is from 25° C.to about 125° C. For example, the temperature of the vacuum oven may beabout 25° C., about 30° C., about 35° C., about 40° C., about 45° C.,about 50° C., about 55° C., about 60° C., about 65° C., about 70° C.,about 75° C., about 80° C., about 85° C., about 90° C., about 90° C.,about 95° C., about 100° C., about 105° C., about 110° C., about 115°C., about 120° C., about 125° C., including subranges and rangestherebetween. In some embodiments, the temperature of the vacuum oven isabout 35° C.

In some embodiments, the same pressures may be used to dry acrystallized cannabinoid using a desiccator or by vacuum filtrationusing a filtration flask.

In some embodiments, the crystallized cannabinoid is homogenized. Insome embodiments, homogenizing a crystallized cannabinoid comprisesbreaking the crystallized cannabinoid apart into small particles. Insome embodiments, the crystallized cannabinoid is homogenized using arotor stator homogenizer (e.g., with the crystals suspended in water).In some embodiments, the crystallized cannabinoid is homogenized at aspeed from about 5000 rpm to about 50,000 rpm, for example, about 5000rpm, about 6000 rpm, about 7000 rpm, about 8000 rpm, about 9000 rpm,about 10,000 rpm, about 11,000 rpm, about 12,000 rpm, about 13,000 rpm,about 14,000 rpm, about 15,000 rpm, about 16,000 rpm, about 17,000 rpm,about 18,000 rpm, about 19,000 rpm, about 20,000 rpm, about 21,000 rpm,about 22,000 rpm, about 23,000 rpm, about 24,000 rpm, about 25,000 rpm,about 26,000 rpm, about 27,000 rpm, about 28,000 rpm, about 29,000 rpm,about 30,000 rpm, about 31,000 rpm, about 32,000 rpm, about 33,000 rpm,about 34,000 rpm, about 35,000 rpm, about 36,000 rpm, about 37,000 rpm,about 38,000 rpm, about 39,000 rpm, about 40,000 rpm, about 41,000 rpm,about 42,000 rpm, about 43,000 rpm, about 44,000 rpm, about 44,000 rpm,about 45,000 rpm, about 46,000 rpm, about 47,000 rpm, about 48,000 rpm,about 49,000 rpm, or about 50,000 rpm, including all values and rangestherebetween. In some embodiments, the crystallized cannabinoid ishomogenized at a speed of 15,000 rpm. In some embodiments, thecrystallized cannabinoid is homogenized for about 1 minute (min) toabout 120 min, for example, about 1 min, about 2 min, about 3 min, about4 min, about 5 min, about 6 min, about 7 min, about 8 min, about 9 min,about 10 min, about 11 min, about 12 min, about 13 min, about 14 min,about 15 min, about 16 min, about 17 min, about 18 min, about 19 min,about 20 min, about 21 min, about 22 min, about 23 min, about 24 min,about 25 min, about 26 min, about 27 min, about 28 min, about 29 min,about 30 min, about 31 min, about 32 min, about 33 min, about 34 min,about 35 min, about 36 min, about 37 min, about 38 min, about 39 min,about 40 min, about 41 min, about 42 min, about 43 min, about 44 min,about 45 min, about 46 min, about 47 min, about 48 min, about 49 min,about 50 min, about 51 min, about 52 min, about 53 min, about 54 min,about 55 min, about 56 min, about 57 min, about 58 min, about 59 min,about 60 min, about 61 min, about 62 min, about 63 min, about 64 min,about 65 min, about 66 min, about 67 min, about 68 min, about 69 min,about 70 min, about 71 min, about 72 min, about 73 min, about 74 min,about 75 min, about 76 min, about 77 min, about 78 min, about 79 min,about 80 min, about 81 min, about 82 min, about 83 min, about 84 min,about 85 min, about 86 min, about 87 min, about 88 min, about 89 min,about 90 min, about 91 min, about 92 min, about 93 min, about 94 min,about 95 min, about 96 min, about 97 min, about 98 min, about 99 min,about 100 min, about 101 min, about 102 min, about 103 min, about 104min, about 105 min, about 106 min, about 107 min, about 108 min, about109 min, about 110 min, about 111 min, about 112 min, about 113 min,about 114 min, about 115 min, about 116 min, about 117 min, about 118min, about 119 min, or about 120 min, including all values and rangestherebetween, inclusive of endpoints.

In some embodiments, the methods of the disclosure provide cannabinoidcompositions containing a substantially pure selected cannabinoid. Insome embodiments, the cannabinoid composition comprises at least about95%, at least about 96%, at least about 97%, at least about 98%, or atleast about 99% of the selected cannabinoid by weight of the solution.In some embodiments, the substantially pure cannabinoid is at leastabout 95%, at least about 96%, at least about 97%, at least about 98%,or at least about 99% pure.

Processing of Byproducts

In some embodiments, byproducts of the methods described herein areprocessed to yield additional products. In some embodiments, the productis a purified cannabinoid, a wax, or a terpene.

In some embodiments, a byproduct is the filtrate resulting from forcingthe crystallized cannabinoid solution through a filter. In someembodiments, the byproduct is processed to selectively crystallizeand/or purify a cannabinoid. In some embodiments, processing thebyproduct comprises (i) subjecting the filtrate to a technique whichresults in a solution comprising a second selected cannabinoid with aconcentration greater than or equal to its supersaturation point; (ii)increasing the temperature of the solution until the second selectedcannabinoid is substantially dissolved in the solution; and (iii)decreasing the temperature of the solution to about −5° C. or lower toproduce a cooled solution wherein the second selected cannabinoidcrystallizes out of solution, thereby forming crystals of the secondselected cannabinoid. In some embodiments, the second selectedcannabinoid is the same as the initial selected cannabinoid that ispurified. In some embodiments, the second selected cannabinoid isdifferent than the initial selected cannabinoid that is purified. Insome embodiments, the technique used to create a solution comprising asecond selected cannabinoid with a concentration greater than or equalto its supersaturation point is distillation, for example, fractionaldistillation. In some embodiments, a mixture comprising crystals of thesecond selected cannabinoid is purified by (i) forcing the mixturethrough a filter, said filter having a pore size smaller than about 2μm; wherein this step is performed at a temperature below the meltingpoint of the second crystallized cannabinoid, wherein the crystallizedcannabinoid remains on the filter; and (ii) collecting the secondcrystallized cannabinoid from the filter, thereby purifying the secondselected cannabinoid.

In some embodiments, washing the crystallized cannabinoid creates abyproduct formed on the surface of the container used for washing. Insome embodiments, the byproduct contains fats and waxes.

EXAMPLES

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby

Example 1A—Crystallization of a Selected Cannabinoid from a SolutionComprising a Plurality of Cannabinoids

CBD was crystallized from a solution comprising a plurality ofcannabinoids. Table A1 shows the cannabinoids within the CBD-richsolution comprising a plurality of cannabinoids. The solution containedCBD at a concentration of 76.87% by weight. The solution of Table A1 washeated to 60° C. until the cannabinoid was substantially dissolved inthe solution (e.g. for about five minutes). The fully dissolved solutionwas then exposed to the following nucleation factors: agitation (intensestirring) and cold shock (cooling the solution to −20° C.).Subsequently, a cannabinoid seed crystal was introduced to the cooledsolution, and the solution was exposed to a vacuum at a pressure of −25inHg and a temperature of 34.4° C. The solution was left in the vacuumovernight. Then, the solution was removed from the vacuum, and thetemperature and pressure were gradually adjusted to ambient temperature(−25° C.) and pressure (1 atm) over the course of two hours. Thesolution was incubated at ambient temperature for 4-10 hours. The methodresulted in the formation of CBD crystals (FIG. 1).

TABLE A1 CBD-rich Solution Comprising a Plurality of Cannabinoids.Compound % by weight (w/w) THCA ND Delta 9-tetrahydrocannabinol (Δ9-THC)3.67 CBDA 1.04 CBD 76.87  Delta 8-tetrahydrocannabinol (Δ8-THC) ND CBNAND CBN 0.13 Cannabigerolic acid (CBGA) ND CBG 1.97 THCVA ND THCV 0.30CBDVA ND CBDV 0.58 CBCA ND CBC 3.95 “ND” refers to a cannabinoid that isnot detected.

THC was crystallized from a solution comprising a plurality ofcannabinoids. FIG. 2 shows an image of THC-rich starting material. TheTHC-rich starting material contained 68% THCA, <1 THC, and <1 THCV. TheTHC-rich solution was heated to 60° C. The solution was mixed until theTHC was dissolved. Subsequently, the heated solution was cold shocked(cooling the solution to −20° C.) and agitated. The cooled mixture wasplaced in a vacuum oven at a temperature of 34.4° C. at a pressure of−25 inHg, and a seed crystal of THC was introduced to the cooledmixture. The temperature and pressure were gradually adjusted to ambienttemperature (−25° C.) and pressure (1 atm) over the course of two hours.The solution was incubated at ambient temperature for 4-10 hours. Thisprocedure resulted in THC crystals (FIG. 3A and FIG. 3B).

Selective crystallization of CBNA, CBN, CBGA, CBG, THCVA, THCV, CBDVA,CBDV, CBCA, and CBD is performed using the methods described above.

Example 1B—A Method of Separating a Selected Cannabinoid from a SolutionComprising a Plurality of Cannabinoids

The THC crystals and CBD crystals formed in Example 1A were separatedfrom solution according to the following method. The solution was placedon a filter with a pore size less than 25 μm (Whatman paper), the filterwas placed above a filtration flask, and the filtration flask was spunin a centrifuge at a speed of 5000 rpm for 90 minutes. Duringcentrifugation, the temperature was increased from ambient temperatureto 40° C. After centrifugation, the solution was cooled to ambienttemperature. Subsequently, the solution was centrifuged again at 5000rpm for 90 minutes.

After centrifugation, the crystallized CBD and/or THC was collected fromthe filter, and the byproduct (e.g. the filtrate) was saved forcrystallization and/or purification of other cannabinoids. Thecrystallized CBD was 91.86% pure. Table A2 shows the composition of theCBD crystals.

TABLE A2 Composition of Cooled Solution Comprising CBD crystals Compound% by weight (w/w) THCA ND Delta 9-tetrahydrocannabinol (Δ9-THC) 0.46CBDA 0.22 CBD 91.86  Delta 8-tetrahydrocannabinol (Δ8-THC) ND CBNA NDCBN ND Cannabigerolic acid (CBGA) ND CBG 0.28 THCVA ND THCV ND CBDVA NDCBDV 0.43 CBCA ND CBC 0.56 “ND” refers to a cannabinoid that is notdetected.

Additional purification/cleanup steps were conducted as follows: the THCand/or CBD powder was washed in water and shaken with a rotostator, andthen centrifuged again. These steps are described below in more detail.

Oils, waxes, fats, and terpenes were removed from the THC and/or CBDcrystals according to the following process. The THC and/or CBD crystalswere placed into a beaker of water at a temperature between 1° C. and 8°C. at a pH of 6.5. A rotor stator homogenizer was applied to the waterfor five minutes at a speed of 15,000 rpm to disperse the CBD and/or THCcrystals throughout the water. The CBD and/or THC mixture was forcedthrough Whatman paper covering a 25 μm filtration flask. The filtratecontained terpenes and fats, and the walls of the beaker of thecontainer contained fats and waxes. The CBD and/or THC remained on thefilter. The CBD and/or THC was washed with water and collected from thefilter. The CBD and/or THC was placed in a vacuum oven to purge waterand dissolved terpenes. FIG. 4A and FIG. 4B show the resultant THCpowder. Table A3 shows the composition of the resultant CBD powder. Thecomposition of CBD contains 0% terpenes by weight.

TABLE A3 Composition of CBD crystals after washing with water and dryingin a vacuum oven Compound % by weight (w/w) THCA ND Delta9-tetrahydrocannabinol (Δ9-THC) 0.49 CBDA 0.16 CBD 95.73  Delta8-tetrahydrocannabinol (Δ8-THC) ND CBNA ND CBN ND Cannabigerolic acid(CBGA) ND CBG ND THCVA ND THCV ND CBDVA ND CBDV 0.42 CBCA ND CBC NDTerpenes ND “ND” refers to a cannabinoid that is not detected.

The CBD and/or THC powder was further refined to remove the residualcannabinoids. Briefly, the method comprised (i) placing the CBD and/orTHC powder on a filter on top of a filtration flask; (ii) centrifugingthe CBD and/or THC powder at 5000 rpm for 90 minutes and increasing thetemperature to 40° C. during centrifugation; (iii) removing the CBDand/or THC powder from the filter, and placing it on a new filter; and(iv) centrifuging the CBD and/or THC powder at 5000 rpm for 90 minutes.The CBD/and or THC powder was removed from the filter and placed in avacuum oven at 33.3° C. and a pressure of −25 inHg for 24 hours. Afterthis refinement step, the CBD was 99.5% pure, and the THC was 100% pure.FIG. 5 shows a picture of the CBD crystals. FIG. 6 shows a picture ofTHC crystals.

CBNA, CBN, CBGA, CBG, THCVA, THCV, CBDVA, CBDV, CBCA, and CBC crystalsare similarly purified from a mixture of cannabinoids using the methodsdescribed above.

Example 2—Effect of Various Nucleation Factors on the Crystallizationand/or Purification of a Selected Cannabinoid

The effect of a nucleation factor on the crystallization and/orpurification of a selected cannabinoid was evaluated. Briefly, asolution comprising a plurality of cannabinoids (i.e., a primarycannabis extract), wherein the selected cannabinoid is present in thesolution at a concentration greater than or equal to its supersaturationpoint, and wherein the selected cannabinoid is the highest concentrationcannabinoid in the solution is provided. All samples containing theplurality of cannabinoids were heated until the selected cannabinoid issubstantially dissolved in the solution (e.g. 60° C. for about fiveminutes). These substantially dissolved solutions were then processedwith one or more of the nucleation factors of the present disclosure,including: cold shock, vacuum, seed crystal, and mechanical agitation.Samples that did not receive cold shock treatment were allowed to coolnaturally to room temperature sitting on the counter before furthernucleation factors were applied. Crystallization of the cannabinoid wasevaluated for each sample after 24 hours. The yield, purity, crystalsize, and homogeneity of the crystals is measured. Experimental designand results are shown in Table A4.

TABLE A4 Solutions Evaluated in Example 2 Photograph of SolutionNucleation after 24 Solutions Factor (s) Observation hours 1 Cold ShockThe oil appears unchanged FIG. 7A (reducing and resembles the controltemperature in every aspect. to −5° C.) Cold shock alone not sufficientto crystallize selected cannabinoid. 2 Vacuum Crystallization did notoccur. FIG. 7B (−20 inHg Vacuum alone was not for 24 hours) sufficientto crystallize the selected cannabinoid in this solution. Withoutwishing to be bound by any theory, Applicant believes that the lack ofmicrobubbles rendered the vacuum ineffective. 3 Agitation Agitation wasvery effective FIG. 7C (intense in rapidly starting crystal stirring)formation. The intense agitation also dissolved microbubbles throughoutthe material which set up nucleation sites for crystallization at normalpressures. The material took on a thicker, more waxy appearance andtexture. The light is much more diffuse across the surface and tightspecular highlights are not seen. From visual inspection, it appearedthat crystallization was incomplete. 4 Seed crystal No crystallization.Seed crystals FIG. 7D alone were insufficient to crystallize theselected cannabinoid. 5 Cold Shock This image shows partial FIG. 7F(reducing microbubble formation that will temperature lead to crystalformation. to −5° C.) However, microbubble Agitation formation isnon-homogenous. (intense This is evident in an image, stirring) becausedifferent sides are Seed Crystal different colors. Additionally, thesurface of the oil has a tight specular sheen. These observations meanthere aren't enough crystals or microbubble sites to diffuse or scatterthe light across the surface. Without being bound by theory, it ispossible that cold shock reduced the effectiveness of agitation (handstirring) for crystallization by thickening the solution, withoutfollowing up with vacuum capable of expanding/propagating themicrobubbles. Stronger agitation of the more viscous cooled solutionwould be expected to increase crystallization. 6 Cold Shock Solution 6formed a crystalline FIG. 7G Agitation solid. The air bubbles within the(intense solution are composed of thin stirring) layers of crystals thathave been Vacuum suspended in a “foam”. This (−20 inHg) productcrystallized top down, with the lower portion being the non-crystallizedcomponents. Solution 6 is ideal for purification. 7 Agitation Once againthis is ideal. The FIG. 7H (intense material has lightened due tostirring) the crystal formation and the Seed crystal rising of thebubbles/foam Vacuum inside of the vacuum oven, (−20 inHg) creating verythin films where crystals form. Solution 7 is ideal for purification.Applicant expects that only agitation and vacuum would also result inviable crystal formation. 8 Cold Shock Solution 8 did not yield a viableFIG. 7I Seed crystal product. The image shows the Vacuum seed crystals,unchanged, and (−20 inHg) with nothing growing from them, as well aslarger bubbles from the vacuum process that do not act as goodnucleation sites for crystal formation. The color is unchanged as thereare no crystals to diffuse, scatter, or bend the light as it passesthrough.

No crystallization of the selected cannabinoid (CBD) was observed usingonly the cold shock nucleation factor (Solution 1, FIG. 7A). Mechanicalagitation of the solution containing the selected cannabinoid (CBD) ledto some crystal formation, but the crystallization was incomplete,leaving a large portion of the selected cannabinoid in solution(Solution 3, FIG. 7C). Introduction of a seed crystal to the solutioncontaining the selected cannabinoid (CBD) was not sufficient tocrystallize the selected cannabinoid within 24 hours (Solution 4, FIG.7D) beyond the initially present seed crystal (Solution 4, FIG. 7E).Introduction of a seed crystal, mechanical agitation, and cold shockresulted in partial crystallization of the selected cannabinoid(Solution 5, FIG. 7F). Mechanical agitation, cold shock, and a vacuumled to complete crystallization within 24 hours. (Solution 6, FIG. 7G).Mechanical agitation, the introduction of a seed crystal, and vacuumresulted in complete crystallization within 24 hours. (Solution 7, FIG.7H). Seed crystal, cold shock, and vacuum resulted in incompletecrystallization within 24 hours. (Solution 8, FIG. 7I). FIG. 7J showscrystallization after 24 hours of samples 8, 7, 6, and 2 (left toright).

Table A5 shows the relative amount of each cannabinoid present in thecrystals after crystallization according to the methods described above.Selective crystallization of samples 3, 6, 7, and 8 resulted inenrichment for the selected cannabinoid (CBD) and a decrease in minorcannabinoids such as THC compared to the starting material (base oil).These analyses were conducted prior to the centrifuge separation stepsdescribed below. Samples 6 and 7 exhibited the highest amount ofcrystallization as a proportion of the sample, resulting in a greater %of recovery of the selected cannabinoid (i.e. greater yield). Thisexperiment showed that mechanical agitation of a solution containing aselected cannabinoid and exposure of the same solution to a vacuumresulted in the best crystal formation and purification. The presence ofa seed crystal may also aid in enhancing the purification of theselected cannabinoid (CBD). The ability of alternate nucleation factorsto influence crystallization, such as increasing/maintaining moisturecontent and aeration of the solution containing the dissolvedcannabinoid, is undergoing validation.

TABLE A5 Cannabinoids Present in Each Crystal after SelectiveCrystallization Solution Component (unit) Base Oil 1 2 3 4 5 6 7 8 CBC(mg/g) 42.7 44 41.2 41.7 48.3 43.4 41.7 41.1 43.0 Cannabicitran 2.122.02 2.06 2.02 2 2.08 2.03 2.12 2.06 (CBT) (mg/g) CBD (mg/g) 693 738 733742 734 736 747 748 751 CBDA (mg/g) 12.5 12.4 12.3 12.6 11.9 12.4 12.312.1 11.4 CBDV (mg/g) 6.27 6.2 6.53 6.08 5.78 5.88 6.35 5.56 5.70 CBG(mg/g) 15.5 15.3 14.8 15.3 14.8 15.3 14.9 14.9 15.0 CBN (mg/g) 2.63 2.022.02 2.06 2.04 2.08 2.00 2.06 2.05 THC 3.61 3.55 3.55 3.51 3.52 3.533.43 3.49 3.34 (% by weight) THCA <0.01 <0.01 <0.01 <0.01 <0.01 <0.01<0.01 <0.01 <0.01 (% by weight) Potential CBD 70.4 74.9 74.4 75.3 74.574.7 75.8 75.9 76.1 (% by weight) Potential THC 3.61 3.55 3.55 3.51 3.523.53 3.43 3.49 3.34 (% by weight) THCV (mg/g) 1.35 1.50 1.33 1.38 1.571.42 1.33 1.32 1.25

Example 3—Selective Crystallization and Purification of a Cannabinoidfrom the Byproduct of Example 1B

The byproduct from the CBD purification described in Example 1B iscollected and used as starting material for the crystallization andpurification of additional cannabinoids. The composition of thebyproduct is shown in Table A6.

TABLE A6 Composition of Byproduct Compound % by weight (w/w) THCA NDDelta 9-tetrahydrocannabinol (Δ9-THC) 6.73 CBDA 1.87 CBD 56.98  Delta8-tetrahydrocannabinol (Δ8-THC) ND CBNA ND CBN 0.25 Cannabigerolic acid(CBGA) ND CBG 3.50 THCVA ND THCV 0.53 CBDVA ND CBDV 0.63 CBCA ND CBC6.76

The byproduct is fractionally distilled to increase the concentration ofa selected cannabinoid, for example, THC, CBDA, CBD, CBN, CBG, THCV,CBDV, or CBC, such that the selected cannabinoid is the highestcannabinoid concentration in the composition and the selectedcannabinoid's concentration is above the supersaturation point of theselected cannabinoid.

The solution containing the selected cannabinoid is heated to between50° C. and 79° C. and mixed until the selected cannabinoid is dissolved.Subsequently, the heated solution is subjected to one or more of thenucleation factors (e.g., vacuum and intense agitation). Thecrystallized selected cannabinoid is then separated from the solution asdescribed in Example 1B.

Example 4—Unpredictable Natural Crystallization of Cannabinoids fromVarious Hemp Oils

The presently disclosed methods provide a fast and reliable method forachieving high levels of crystallization of selected cannabinoidswithout the use of exogenous solvents. Persons having skill in the artwill be aware that cannabinoid solutions, such as cannabinoid extractsare capable of naturally crystallizing over time. Thesecrystallizations, however, occur slowly, are highly unpredictable,result in non-homogenous and often contaminated crystals, and incompletecrystallization. This example tests the natural crystallization ofvarious samples to provide a comparison point against the artificiallyinduced crystallizations achieved by the presently disclosed methods.

100 grams of each of ten different hemp oil samples (referred to assample, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) were heated to a temperatureof 60° C. and incubated for five minutes. Each hemp oil sample wassubsequently incubated at room temperature and observed visually every12 hours. None of the ten samples formed crystals after 4 days. After 95days, samples 9 (FIG. 15A), 4 (FIG. 15B), 1 (FIG. 15C), and 8 (FIG. 15D)crystallized, and samples 2 (FIG. 15E), 5 (FIG. 15F), 3 (FIG. 15G), 6(FIG. 15H), 7 (FIG. 15I), and 10 (FIG. 15J) did not crystallize. Thisexample highlights the unpredictability of natural crystallization.

Example 5—Nucleation Factors Improve Crystallization

Crystallization of CBD from a CBD solution in the absence and presenceof nucleation factors was evaluated. A first sample of the CBD solutionwas not exposed to any nucleation factors. The first sample was heatedto 60° C., incubated for five minutes, and allowed to cool to roomtemperature. A second sample of the CBD solution was heated to 60° C.until the CBD was dissolved in the solution and subsequently exposed tothe following nucleation factors: cold shock, agitation, seed crystal,and a vacuum of −25 inHg. Cold shock entailed cooling the heatedsolution to −20° C. and agitation was conducted via vigorous handmixing.

After 24 hours, in the absence of nucleation factors, visual inspectionof the CBD solution appeared to show that the CBD remained in solution(FIG. 11A). In contrast, CBD crystallized in the presence of nucleationfactors started forming light crystals within 1 hour (FIG. 11B).

Each sample was subsequently analyzed with a microscope. Under themicroscope, the first sample, which was not exposed to nucleationfactors, contained some microscopic heterogeneous crystals that weresmaller than 25 μm in size (FIG. 11D). These crystals were alsocontaminated by oils. The sample that is not exposed to nucleationfactors is not ideal for cannabinoid purification. In contrast, when thesecond sample that is exposed to nucleation factors is evaluated underthe microscope, homogeneous crystals are observed that are the idealsize for purification (≥25 μm in size) (FIG. 11C). The crystals werealso clean, clear, and pure.

Example 6A—Determination of the Minimum Concentration of CannabinoidRequired for Crystallization when the Cannabinoid is the OnlyCannabinoid in the Solution

The minimum concentration required to crystallize a cannabinoid (e.g.,CBD and THCA) in a solution containing only one cannabinoid wasdetermined by evaluating the ability of the cannabinoid (e.g., CBD orTHCA) to crystallize at various concentrations. The ability of solutionscontaining about 75%, about 70%, about 65%, about 60%, about 55%, about50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%,about 15%, about 10%, or about 5% of a selected cannabinoid wasevaluated. The cannabinoids were suspended in oleic acid. All sampleswere heated until the cannabinoid was substantially dissolved in thesolution (e.g. 60° C. for about five minutes). These fully dissolvedsolutions were then exposed to the following nucleation factors:agitation (intense stirring), cold shock (cooling the solution to −20°C. and mixing), introduction of a cannabinoid seed crystal, and exposureto a vacuum at a pressure of −25 inHg). Photographs of the crystallizedcannabinoids were taken after 24 hours.

CBD crystallized from solutions containing 60% CBD (FIG. 12A), 50% CBD(FIG. 12B), 40% CBD (FIG. 12C), and 30% CBD (FIG. 12D). Similarly, THCAcrystallized from solutions containing 60% THCA (FIG. 13A), 50% THCA(FIG. 13B), 40% THCA (FIG. 13C), and 30% THCA (FIG. 13D). Thus, alltested concentrations of THCA and CBD crystallized. As expected, higherconcentration solutions exhibited more crystals in solution.

Example 6B—Determination of the Minimum Concentration of SelectedCannabinoid Required for Crystallization from a Solution Containing aPlurality of Cannabinoids

The minimum concentration of CBD required for selective crystallizationfrom a solution containing a plurality of cannabinoids was evaluated.The composition of the CBD-rich solution comprising a plurality ofcannabinoids is shown in Table A7.

TABLE A7 CBD-rich Solution Comprising a Plurality of Cannabinoids.Compound % by weight (w/w) THCA ND Delta 9-tetrahydrocannabinol (Δ9-THC)3.85 CBDA 0.83 CBD 78.25  Delta 8-tetrahydrocannabinol (Δ8-THC) ND CBNAND CBN ND Cannabigerolic acid (CBGA) ND CBG 1.74 THCVA ND THCV 0.24CBDVA ND CBDV 0.54 CBCA ND CBC 3.68 “ND” refers to a cannabinoid that isnot detected.

The ability of CBD to crystallize at the following concentrations wasevaluated: 31.3% w/w, 19.6% w/w, 15.7% w/w, 11.7% w/w, 7.8% w/w, and3.9% w/w. was evaluated. The CBD-rich solution shown in Table A7 wasdiluted in MCT coconut oil to the aforementioned CBD concentrations. Thesamples were heated to 60° C. for about five minutes. Then, eachsolution was subjected to the following nucleation factors: agitation(intense stirring), cold shock (cooling solution to −20° C. and mixing),introduction of a CBD seed crystal, and exposure to a vacuum at apressure of −25 inHg). Photographs of the crystallized cannabinoids weretaken after 24 hours. Table A8 summarizes observations of the solutionsat each CBD concentration.

TABLE A8 Observation of Crystallization of CBD from CBD-rich SolutionComprising a Plurality of Cannabinoids CBD Concentration (% w/w)Observation FIG. 31.3 CBD crystallized. The crystals FIG. 14A can beisolated using the protocol of Example 1B. 19.6 CBD crystallized. Thecrystals FIG. 14B can be isolated using the protocol of Example 1B. 15.7CBD did not crystallize after FIG. 14C 24 hours. 11.7 CBD did notcrystallize after FIG. 14D 24 hours. 7.8 CBD did not crystallize afterFIG. 14E 24 hours. 3.9 CBD did not crystallize after FIG. 14F 24 hours.

The lowest tested concentration of CBD in MCT oil that exhibitedcrystallization via the presently claimed methods was 19.6%. Theexperiment was also repeated using mixtures of cannabinoid CBD and THCaisolates in oleic acid. The lowest tested concentration of CBD thatcrystallized was 24% (FIG. 16), though lower concentrations may alsocrystallize if tested.

These results were surprising, because traditional solvent-based methodsrequire a minimum selected cannabinoid concentration of at least 80%.The results also demonstrated that the crystallization methods work indifferent solvents, and in solutions that are completely free from othercompounds other than cannabinoids, or in complex mixtures, such asprimary cannabinoid extracts.

This process is repeated to determine the minimum concentration ofcrystallization for alternative cannabinoids, including THC, THCV, CBDA,CBDV, THCA, CBG, CBN, CBDVA, CBNA, CBGA, CBCA, and CBC. This process isalso repeated to determine the minimum concentration of crystallizationof cannabinoids in alternative solvents, such as olive oil, coconut oil,canola oil, flaxseed oil, avocado oil, sesame oil, canola oil, palm oil,safflower oil, soybean oil, corn oil, peanut oil, walnut oil, flaxseedoil, sunflower oil, palm oil, palm kernel oil, caproic acid, caprylicacid, hempseed oil, and walnut oil.

Example 7—Effect of Vacuum Strength on Crystallization of a SelectedCannabinoid

The effect of vacuum strength on cannabinoid crystallization wasevaluated. All samples were heated to 60° C. for about five minutes.Each solution was then subjected to the following nucleation factors:agitation (intense stirring), cold shock (cooling solution to −20° C.and mixing), introduction of a CBD seed crystal, and exposure to avacuum oven at a temperature of 34.4° C. for one hour. The followingvacuum oven pressures were evaluated: −5 inHg (FIG. 8A), −10 inHg (FIG.8B), −15 inHg (FIG. 8C), and −20 inHg (FIG. 8D) vacuum.

Cannabinoid crystals exhibit a matte finish, are opaque, have a firmtexture, and contain microbubbles. These factors were used to evaluateoverall crystallization.

Exposure to all four vacuum pressures resulted in crystallization.Higher vacuum pressures increased the rate of crystallization, which ledto the appearance of crystals that appeared matte.

Example 8—Effect of Rotor Stator Homogenizer on Crystal Appearance andPurity

CBD was crystallized from a solution containing a plurality ofcannabinoids according to the methods of Example 1A. CBD crystals wereseparated from solution according to the following method. The solutionwas placed on a filter with a pore size less than 25 μm (Whatman paper),the filter was placed above a filtration flask, and the filtration flaskwas spun in a centrifuge at a speed of 5000 rpm for 90 minutes. Duringcentrifugation, the temperature was increased from ambient temperatureto 40° C. After centrifugation, the solution was cooled to ambienttemperature. Subsequently, the solution was centrifuged again at 5000rpm for 90 minutes. During centrifugation, the temperature was increasedfrom ambient temperature to 40° C. After centrifugation, thecrystallized CBD was collected from the filter.

The CBD was subsequently placed into a beaker of water at a temperaturebetween 1° C. and 8° C. at a pH of 6.5 with or without a rotor statorhomogenizer. If the rotor stator homogenizer was applied to the watercontaining the CBD crystals, it was applied to the water for fiveminutes at a speed of 15,000 rpm to disperse the cannabinoid crystalsthroughout the water. After washing, the CBD mixture was forced througha Whatman paper covering over a 25 μm filtration flask to remove thewater. The CBD was collected from the Whatman paper and desiccated toremove any remaining traces of water. The appearance of the crystals wasvisualized, and the purity of the CBD was determined. The CBD crystalsthat were washed in the presence of a rotor stator homogenizer wasbrilliant white with no smell (FIG. 9A). In contrast, CBD crystalswashed in the absence of a rotor stator homogenizer were off-white withlarger clumps and a characteristic hemp smell (FIG. 9B). Washing in thepresence of a rotor stator homogenizer increased the purity of the CBD(Table A9) by 1.3%. Washing also reduced the oil content of the CBDcrystals, as determined visually in FIG. 9A and FIG. 9B. As noted above,the consumer qualities of the crystals were significantly improved bythe rotostator wash. Persons having skill in the art will recognizeother tools that could be used to disperse/mix the crystals with water.Cannabinoid crystals are insoluble in water. Persons having skill in theart will be aware of other solvents that could be used in this wash.

TABLE A9 Cannabinoids Present in Each Solution after Washing with orwithout a Rotor Stator Homogenizer Washing in the Washing in thepresence of a rotor absence of a rotor Component (unit) statorhomogenizer stator homogenizer CBC (mg/g) 4.81 4.67 Cannabicitran (CBT)(mg/g) 0.293 0.239 CBD (mg/g) 936 923 CBDA (mg/g) 2.19 2.00 CBDV (mg/g)5.33 5.31 CBG (mg/g) 1.79 1.77 CBN (mg/g) 0.335 0.316 THC (% by weight)0.468 0.467 THCA (% by weight) <0.01 <0.01 Potential CBD (% by weight)93.7 92.5 Potential THC (% by weight) 0.468 0.467 THCV (mg/g) 0.8240.679

Example 9—Comparing the Effect of Filtration Techniques on Purity andAppearance of CBD Crystals

CBD was crystallized from a solution containing a plurality ofcannabinoids according to the methods of Example 1A. The solution wasdivided into two samples, and the CBD crystals of each sample wereseparated from solution.

In one sample, the CBD crystals were separated from solution accordingto the following method. The solution was placed on a filter with a poresize less than 25 μm (Whatman paper), the filter was placed above afiltration flask, and the filtration flask was spun in a centrifuge at aspeed of 5000 rpm for 90 minutes. During centrifugation, the temperaturewas increased from ambient temperature to 40° C. After centrifugation,the solution was cooled to ambient temperature. Subsequently, thesolution was centrifuged again at 5000 rpm for 90 minutes. Duringcentrifugation, the temperature was increased from ambient temperatureto 40° C. After centrifugation, the crystallized CBD was collected fromthe filter.

In the other sample, CBD was separated from the solution using vacuumfiltration. The CBD crystals obtained from each method were desiccated.

The purity and appearance of each sample was compared.

Separation of the CBD crystals from solution using the centrifugationprocedure resulted in brilliant white, dry CBD crystals that did nothave a smell (FIG. 10A). Separation of the CBD crystals from solutionusing vacuum filtration resulted in orange-yellow CBD crystals that wereoily to the touch (FIG. 10B). Separation of the CBD crystals fromsolution by centrifugation resulted in the formation of CBD crystalsthat were more pure, e.g., 94.6% pure, than CBD crystals separated fromsolution by vacuum filtration, e.g., 76.2% pure. Separation of the CBDcrystals from solution by centrifugation also resulted in a superiorremoval of terpenes than CBD crystals separated from solution by vacuumfiltration. The cannabinoid profile and terpene profile of the crystalsare displayed in Table A10 and Table A11, respectively.

TABLE A10 Cannabinoids Present in Each Solution after Centrifugation orVacuum Filtration CBD Crystals CBD Crystals Isolated from Isolated fromsolution by solution by Cannabinoid (unit) centrifugation vacuumfiltration CBC (mg/g) 4.68 39.5 Cannabicitran (CBT) (mg/g) 0.248 2.08CBD (mg/g) 945 752 CBDA (mg/g) 1.93 11.9 CBDV (mg/g) 5.17 5.48 CBG(mg/g) 1.71 15.2 CBN (mg/g) 0.351 1.99 THC (% by weight) 0.447 3.47 THCA(% by weight) <0.01 <0.01 Potential CBD (% by weight) 94.6 76.2Potential THC (% by weight) 0.447 3.47 THCV (mg/g) 0.85 1.38

TABLE A11 Terpenes Present in Each Solution after Centrifugation orVacuum Filtration CBD Crystals CBD Crystals Isolated from Isolated fromsolution by solution by Terpene (unit) centrifugation vacuum filtration(−)-alpha-bisabolol 20.7 mg/kg 118 mg/kg (−)-beta-pinene ND 0.2 mg/kg(−)-guaiol 25.6 mg/kg 52.2 mg/kg (−)-isopulegol ND ND Alpha-humulene 6.7mg/kg 45.2 mg/kg Alpha-pinene ND ND Alpha-terpinene 4.1 mg/kg 6.1 mg/kgBeta-caryophyllene 18.4 mg/kg 106 mg/kg Beta-myrcene ND 11.4 mg/kgCamphene ND ND Delta-3-carene 1.0 mg/kg 1.7 mg/kg d-limonene 2.5 mg/kg4.1 mg/kg Gamma-terpinene 2.2 mg/kg 3.5 mg/kg Geraniol ND ND Linalool33.1 mg/kg 33.1 mg/kg Nerolidol ND 48.9 mg/kg Ocimene ND NDp-isopropyltoluene ND ND (p-cymene) terpinolene 2.6 mg/kg 3.1 mg/kg

INCORPORATION BY REFERENCE

All references, articles, publications, patents, patent publications,and patent applications cited herein are incorporated by reference intheir entireties for all purposes. However, mention of any reference,article, publication, patent, patent publication, and patent applicationcited herein is not, and should not be taken as, an acknowledgment orany form of suggestion that they constitute valid prior art or form partof the common general knowledge in any country in the world.

Additional Numbered Embodiments of the Invention

The following embodiments are also envisioned by the present disclosure:

1. A method of crystallizing a selected cannabinoid from a cannabinoidsolution, comprising:

(a) providing a solution containing a substantially dissolved selectedcannabinoid;

(b) exposing the dissolved cannabinoid solution of step (a) to a vacuumfor a time period sufficient to crystallize the selected cannabinoid.

1.1 The method of embodiment 1, wherein the solution containing asubstantially dissolved cannabinoid contains microbubbles or dissolvedair that causes bubbling of the solution when exposed to vacuum.2. The method of embodiment 1 or 1.1, wherein the solution comprises aplurality of cannabinoids, wherein the selected cannabinoid is presentin the solution at a concentration greater than or equal to itssupersaturation point, and wherein the selected cannabinoid is thehighest concentration cannabinoid in the solution.2.1 The method of any one of embodiments 1-2, wherein said solution issubstantially free of any exogenous solvent.3. The method of embodiment 2 or 2.1, wherein the supersaturation pointis greater than or equal to 19%, or 30% by weight of the solution.3.1 The method of embodiment 2 or 2.1, wherein the supersaturation pointis greater than or equal to 24% by weight of the solution.4. The method of any one of embodiments 1-3.1, wherein the solution of(a) is produced by increasing the temperature of the cannabinoidsolution until the selected cannabinoid is substantially dissolved inthe solution.5. The method of any one of embodiments 1-4, wherein the time periodsufficient to crystallize the selected cannabinoid is about 15 minutes,about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 3hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about8 hours, about 9 hours, about 10 hours, or more.6. The method of any one of embodiments 1-5, wherein the cannabinoidsolution is a primary cannabis extract.6.1 The method of embodiment 6, wherein the primary cannabis extract isa CO2 extraction or an alcohol extraction of a cannabis plant.6.2 The method of embodiment 6, wherein the primary cannabis extract isa CO2 extraction or an alcohol extraction of a cannabinoid-producingmicroorganism culture.7. The method of any one of embodiments 4-6.2, wherein the temperatureis increased to between about 50° C. and about 79° C.8. The method of any one of embodiments 1-7, comprising exposing thedissolved cannabinoid solution to an additional nucleation factor afterstep (b), wherein the nucleation factor is selected from the groupconsisting of: cold shock, introducing a crystal of the selectedcannabinoid into the dissolved cannabinoid solution (seed crystal),mechanically agitating the dissolved cannabinoid solution, andcombinations thereof.9. The method of any one of embodiments 1-7, comprising exposing thedissolved cannabinoid solution to an additional nucleation factor beforestep (b), wherein the nucleation factor is selected from the groupconsisting of: cold shock, introducing a crystal of the selectedcannabinoid into the dissolved cannabinoid solution (seed crystal),mechanically agitating the dissolved cannabinoid solution, andcombinations thereof.10. The method of any one of embodiments 1-7, comprising mechanicallyagitating the dissolved cannabinoid solution before step (b).11. The method of any one of embodiments 1-7, comprising mechanicallyagitating the dissolved cannabinoid solution after step (b).12. The method of any one of embodiments 1-11, comprising exposing thedissolved cannabinoid solution to an additional nucleation factor afterstep (b), wherein the nucleation factor is selected from the groupconsisting of: increasing or maintaining the moisture content of thesolution, aerating the solution, and combinations thereof.13. The method of any one of embodiments 1-11, comprising exposing thedissolved cannabinoid solution to an additional nucleation factor beforestep (b), wherein the nucleation factor is selected from the groupconsisting of: increasing or maintaining the moisture content of thesolution, aerating the solution, and combinations thereof.14. The method of any one of embodiments 1-13, wherein the selectedcannabinoid is selected from the group consisting of cannabidiol (CBD),tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV), cannabidiolicacid (CBDA), cannabidivarin (CBDV), tetrahydrocannabinolic acid (THCA),cannabigerol (CBG), cannabinol (CBN), cannabinolic acid (CBNA),cannabidivarinic acid (CBDVA), cannabigerolic acid (CBGA),cannabichromenic acid (CBCA), and cannabichromene (CBC).15. The method of any one of embodiments 1-14, wherein the cannabinoidsolution is a Cannabis oil that is substantially free of cutting agents.16. The method of any one of embodiments 1-15, wherein the cannabinoidsolution comprises less than 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%,0.3%, 0.2%, or 0.1% by weight of exogenous solvents.17. The method of any one of embodiments 1-16, wherein at least 80% ofthe selected cannabinoid is crystallized out of the solution.18. The method of any one of embodiments 1-17, wherein the selectedcannabinoid is crystallized out of solution within about 10 hours.19. The method of any one of embodiments 1-18, wherein crystals of theselected cannabinoid comprise crystals that are greater than or equal toabout 25 μm in size.20. The method of any one of embodiments 1-19, wherein the vacuum isgreater than about −5 inHg, about −10 inHg, about −15 inHg, about −20inHg, or about −25 inHg.21. The method of any one of embodiments 1-20, wherein the selectedcannabinoid is at least about 75%, at least about 80%, at least about85%, at least about 90%, at least about 95%, or about 100% dissolved inthe solution at the time step (a) is performed.21.1. The method of any one of embodiments 1-21, wherein the selectedcannabinoid is selectively crystallized from the cannabinoid solution.22. A method of crystallizing a selected cannabinoid from a cannabinoidsolution, said method comprising:

(a) providing a solution containing a substantially dissolved selectedcannabinoid; and

(b) exposing the dissolved cannabinoid solution of step (a) to anucleation factor for a time period sufficient to crystallize theselected cannabinoid, wherein the nucleation factor is selected from thegroup consisting of vacuum, cold shock, introducing a crystal of theselected cannabinoid into the dissolved cannabinoid solution (seedcrystal), mechanically agitating the dissolved cannabinoid solution, andcombinations thereof.

22.1 The method of embodiment 22, wherein the solution containing asubstantially dissolved cannabinoid contains microbubbles or dissolvedair that causes bubbling of the solution when exposed to vacuum.23. The method of embodiment 22 or 22.1, wherein the solution comprisesa plurality of cannabinoids, wherein the selected cannabinoid is presentin the solution at a concentration greater than or equal to itssupersaturation point, and wherein the selected cannabinoid is thehighest concentration cannabinoid in the solution.23.1 The method of any one of embodiments 22-23, wherein said solutionis substantially free of any exogenous solvent.24. The method of embodiment 23 or 23.1, wherein the supersaturationpoint is greater than or equal to 19%, or 30% by weight of the solution.24.1 The method of embodiment 23, 23.1, or 24, wherein thesupersaturation point is greater than or equal to 24% by weight of thesolution.25. The method of any one of embodiments 22-24.1, wherein thecannabinoid solution of (a) is produced by increasing the temperature ofthe cannabinoid solution until the selected cannabinoid is substantiallydissolved in the solution.26. The method of any one of embodiments 22-25, wherein at least 50% ofthe selected cannabinoid is crystallized within about 15 minutes, about30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 3hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about8 hours, about 9 hours, or about 10 hours.27. The method of any one of embodiments 22-26, wherein the cannabinoidsolution is a primary cannabis extract.27.1 The method of embodiment 27, wherein the primary cannabis extractis a CO2 extraction or an alcohol extraction of a cannabis plant.27.2 The method of embodiment 27, wherein the primary cannabis extractis a CO2 extraction or an alcohol extraction of a cannabinoid-producingmicroorganism culture.28. The method of any one of embodiments 25-27.2, wherein thetemperature is increased to between about 50° C. and about 79° C.29. The method of any one of embodiments 22-28, comprising exposing thedissolved cannabinoid solution to an additional nucleation factor afterstep (b), wherein the nucleation factor is selected from the groupconsisting of: increasing or maintaining the moisture content of thesolution, aerating the solution, and combinations thereof.30. The method of any one of embodiments 22-28, comprising exposing thedissolved cannabinoid solution to an additional nucleation factor beforestep (b), wherein the nucleation factor is increasing or maintaining themoisture content of the solution, aerating the solution, andcombinations thereof.31. The method of any one of embodiments 22-30, wherein the selectedcannabinoid is selected from the group consisting of cannabidiol (CBD),tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV), cannabidiolicacid (CBDA), cannabidivarin (CBDV), tetrahydrocannabinolic acid (THCA),cannabigerol (CBG), cannabinol (CBN), cannabinolic acid (CBNA),cannabidivarinic acid (CBDVA), cannabigerolic acid (CBGA),cannabichromenic acid (CBCA), and cannabichromene (CBC).32. The method of any one of embodiments 22-31, wherein the cannabinoidsolution is a Cannabis oil that is substantially free of cutting agents.33. The method of any one of embodiments 22-32, wherein the cannabinoidsolution comprises less than 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%,0.3%, 0.2%, or 0.1% exogenous solvents by weight.34. The method of any one of embodiments 22-33, wherein at least 80% ofthe selected cannabinoid is crystallized out of the cannabinoidsolution.35. The method of any one of embodiments 22-34, wherein at least 50% ofthe selected cannabinoid crystalized out of solution within about 10hours.36. The method of any one of embodiments 22-35, wherein the crystals ofthe selected cannabinoid comprise crystals that are greater than orequal to about 25 μm in size.37. The method of any one of embodiments 22-36, wherein the nucleationfactor is vacuum.38. The method of embodiment 37, wherein the vacuum is greater thanabout −5 inHg, about −10 inHg, about −15 inHg, about −20 inHg, or about−25 inHg.39. The method of any one of embodiments 22-38, wherein the selectedcannabinoid is at least about 75%, at least about 80%, at least about85%, at least about 90%, at least about 95%, or about 100% dissolved inthe cannabinoid solution at the time step (a) is performed.39.1. The method of any one of embodiments 22-39, wherein the selectedcannabinoid is selectively crystallized from the cannabinoid solution.40. A method of purifying a selected cannabinoid from a mixture ofcannabinoids, said method comprising:

(a) providing a mixture of cannabinoids comprising a crystallizedcannabinoid, wherein the crystallized cannabinoid comprises crystalsthat are at least about 25 μm in size;

(b) forcing the mixture of cannabinoids through a filter, said filterhaving a pore size smaller than about 25 μm; wherein this step isperformed at a temperature below the melting point of the crystallizedcannabinoid, wherein the crystallized cannabinoid remains on the filter;and

(c) collecting the crystallized cannabinoid from the filter, therebypurifying the selected cannabinoid.

41. The method of embodiment 40, wherein the crystallized cannabinoid isproduced by the method of any one of embodiments 1-39.42. The method of embodiment 40 or 41, wherein step (b) is performedbetween about 0.5° C. and 10° C. below the melting point of thecrystallized cannabinoid.43. The method of any one of embodiments 40-42, wherein the selectedcannabinoid is selected from the group consisting of consisting ofcannabidiol (CBD), tetrahydrocannabinol (THC), tetrahydrocannabivarin(THCV), cannabidiolic acid (CBDA), cannabidivarin (CBDV),tetrahydrocannabinolic acid (THCA), cannabigerol (CBG), cannabigerolicacid (CBGA), cannabinol (CBN), cannabinolic acid (CBNA),cannabidivarinic acid (CBDVA), cannabichromenic acid (CBCA), andcannabichromene (CBC).44. The method of any one of embodiments 40-43, comprising forcing themixture of cannabinoids through the filter via centrifugation,application of pressure, or application of a vacuum.45. The method of any one of embodiments 40-43, comprising forcing themixture of cannabinoids through the filter via centrifugation.46. The method of any one of embodiments 40-45, comprising washing thecrystallized cannabinoid with a solvent.47. The method of any one of embodiments 40-46, wherein the collectedcrystallized cannabinoid is at least 98% pure by weight.48. A method of purifying a selected cannabinoid from a cannabinoidsolution, said method comprising:

(a) crystallizing the selected cannabinoid from the cannabinoid solutionby exposing the cannabinoid solution to a vacuum for a time periodsufficient to crystallize the selected cannabinoid, thereby producingcannabinoid crystals; and

(b) separating the selected cannabinoid crystals from the cannabinoidsolution;

wherein the selected cannabinoid is substantially dissolved in thecannabinoid solution at the time of step (a).

48.1 The method of embodiment 48, wherein the solution containing asubstantially dissolved cannabinoid contains microbubbles or dissolvedair that causes bubbling of the solution when exposed to vacuum.49. The method of embodiment 48 or 48.1, wherein the cannabinoidsolution comprises a plurality of cannabinoids, wherein the selectedcannabinoid is present in the solution at a concentration greater thanor equal to its supersaturation point, and wherein the selectedcannabinoid is the highest concentration cannabinoid in the solution,and wherein said cannabinoid solution is substantially free of anyexogenous solvent.49.1 The method of any one of embodiments 48-49, wherein said solutionis substantially free of any exogenous solvent.50. The method of embodiment 49 or 49.1, wherein the supersaturationpoint is greater than or equal to 19%, or 30%, by weight of thecannabinoid solution.50.1 The method of any one of embodiments 49-50, wherein thesupersaturation point is greater than or equal to 24% by weight of thecannabinoid solution.51. The method of any one of embodiments 48-50.1, wherein thecannabinoid solution of (a) is produced by increasing the temperature ofthe cannabinoid solution until the selected cannabinoid is substantiallydissolved in the solution.52. The method of any one of embodiments 48-51, wherein at least 95% ofthe selected cannabinoid crystallizes out of the solution intocannabinoid crystals.53. The method of any one of embodiments 48-52, wherein step (b)comprises:

(i) forcing the cannabinoid solution through a filter; wherein this stepis performed at a temperature below the melting point of thecrystallized cannabinoid; and

(ii) collecting the crystallized cannabinoid from the filter, therebyseparating the selected cannabinoid from the cannabinoid solution.

54. The method of embodiment 53, comprising forcing the cannabinoidsolution through the filter via centrifugation, application of pressure,or application of a vacuum.55. The method of embodiment 53, comprising forcing the cannabinoidsolution through the filter via centrifugation.56. The method of any one of embodiments 48-55, wherein the filtercomprises a pore size that is smaller than 2 μm.57. The method of any one of embodiments 48-56, wherein the cannabinoidsolution of (a) is produced by increasing the temperature of thesolution to between about 50° C. and about 79° C.58. The method of any one of embodiments 48-57, comprising exposing thecannabinoid solution to an additional nucleation factor after step (a),wherein the nucleation factor is selected from the group consisting of:cold shock, introducing a crystal of the selected cannabinoid into thedissolved cannabinoid solution (seed crystal), mechanically agitatingthe dissolved cannabinoid solution, and combinations thereof.59. The method of any one of embodiments 48-57, comprising exposing thecannabinoid solution to an additional nucleation factor before step (a),wherein the nucleation factor is selected from the group consisting of:cold shock, introducing a crystal of the selected cannabinoid into thedissolved cannabinoid solution (seed crystal), mechanically agitatingthe dissolved cannabinoid solution, and combinations thereof.60. The method of any one of embodiments 48-59, comprising exposing thecannabinoid solution to an additional nucleation factor after step (a),wherein the nucleation factor is increasing or maintaining the moisturecontent of the solution, aerating the solution, and combinationsthereof.61. The method of any one of embodiments 48-59, comprising exposing thecannabinoid solution to an additional nucleation factor before step (a),wherein the nucleation factor is increasing or maintaining the moisturecontent of the solution, aerating the solution, and combinationsthereof.62. The method of any one of embodiments 48-61, wherein the selectedcannabinoid is selected from the group consisting of cannabidiol (CBD),tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV), cannabidiolicacid (CBDA), cannabidivarin (CBDV), tetrahydrocannabinolic acid (THCA),cannabigerol (CBG), cannabigerolic acid (CBGA), cannabinol (CBN),cannabinolic acid (CBNA), cannabidivarinic acid (CBDVA),cannabichromenic acid (CBCA), and cannabichromene (CBC).63. The method of any one of embodiments 48-62, wherein the cannabinoidsolution is a Cannabis oil that does not contain any cutting agents.63.1 The method of any one of embodiments 48-63, wherein the cannabinoidsolution is a primary cannabis extract.63.2 The method of embodiment 63.1, wherein the primary cannabis extractis a CO2 extraction or an alcohol extraction of a cannabis plant.63.3 The method of embodiment 63.1, wherein the primary cannabis extractis a CO2 extraction or an alcohol extraction of a cannabinoid-producingmicroorganism culture.64. The method of any one of embodiments 48-63.3, wherein thecannabinoid solution comprises less than 1%, 0.9%, 0.8%, 0.7%, 0.6%,0.5%, 0.4%, 0.3%, 0.2%, or 0.1% exogenous solvents by weight.65. The method of any one of embodiments 48-64, wherein at least 95% ofthe selected cannabinoid is crystallized out of the solution.66. The method any one of embodiments 48-65, wherein at least 50% of theselected cannabinoid crystallizes out of solution within about 10 hours.67. The method of any one of embodiments 48-66 wherein the crystals ofthe selected cannabinoid comprise crystals that are at least about 25 μmin size.68. The method of any one of embodiments 48-67, wherein the mixture ofcannabinoids is forced through the filter via centrifugation.68.1 The method of any one of embodiments 48-68, wherein the selectedcannabinoid is selectively crystallized from the cannabinoid solution.69. A method of purifying a selected cannabinoid from a cannabinoidsolution, said method comprising:

(a) crystallizing the selected cannabinoid from the solution by:exposing the cannabinoid solution to a nucleation factor for a timeperiod sufficient to crystallize the selected cannabinoid, wherein thenucleation factor is selected from the group consisting of vacuum, coldshock, introducing a crystal of the selected cannabinoid into thecannabinoid solution (seed crystal), mechanically agitating thecannabinoid solution, and combinations thereof for a time periodsufficient to crystallize the selected cannabinoid, thereby producingcannabinoid crystals; and

(b) separating the selected cannabinoid crystals from the cannabinoidsolution;

wherein the selected cannabinoid is substantially dissolved in thecannabinoid solution at the time of step (a).69.1 The method of embodiment 69, wherein the solution containing asubstantially dissolved cannabinoid contains microbubbles or dissolvedair that causes bubbling of the solution when exposed to vacuum.70. The method of embodiment 69 or 69.1, wherein the cannabinoidsolution comprises a plurality of cannabinoids, wherein the selectedcannabinoid is present in the solution at a concentration greater thanor equal to its supersaturation point, and wherein the selectedcannabinoid is the highest concentration cannabinoid in the solution.70.1 The method of any one of embodiments 69-70, wherein said solutionis substantially free of any exogenous solvent.71. The method of embodiment 70 or 70.1, wherein the supersaturationpoint is greater than or equal to 19%, or 30%, by weight of thesolution.71.1 The method of embodiment 70 or 70.1, wherein the supersaturationpoint is greater than or equal to 24% by weight of the solution.72. The method of any one of embodiments 69-71.1, wherein thecannabinoid solution of step (a) is produced by increasing thetemperature of the cannabinoid solution until the selected cannabinoidis substantially dissolved in the solution.73. The method of any one of embodiments 69-72, wherein at least 95% ofthe selected cannabinoid crystallizes out of the solution intocannabinoid crystals.74. The method of any one of embodiments 69-73, wherein step (b)comprises:(i) forcing the cannabinoid solution through a filter; wherein this stepis performed at a temperature below the melting point of thecrystallized cannabinoid; and(ii) collecting the crystallized cannabinoid from the filter, therebyseparating the selected cannabinoid from the cannabinoid solution.75. The method of embodiment 74, comprising forcing the cannabinoidsolution through the filter via centrifugation, application of pressure,or application of a vacuum.76. The method of embodiment 74, comprising forcing the cannabinoidsolution through the filter via centrifugation.77. The method of any one of embodiments 74-76, wherein the filtercomprises a pore size that is smaller than 2 μm.78. The method of any one of embodiments 69-77, wherein the cannabinoidsolution of step (a) is produced by increasing the temperature of thesolution to between about 50° C. and about 79° C.79. The method of any one of embodiments 69-78, comprising exposing thecannabinoid solution to an additional nucleation factor after step (a),wherein the nucleation factor is increasing or maintaining the moisturecontent of the solution, aerating the solution, and combinationsthereof.80. The method of any one of embodiments 69-78, comprising exposing thecannabinoid solution to an additional nucleation factor before step (a),wherein the nucleation factor is increasing or maintaining the moisturecontent of the solution, aerating the solution, and combinationsthereof.81. The method of any one of embodiments 69-80, wherein the selectedcannabinoid is selected from the group consisting of cannabidiol (CBD),tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV), cannabidiolicacid (CBDA), cannabidivarin (CBDV), tetrahydrocannabinolic acid (THCA),cannabigerol (CBG), cannabigerolic acid (CBGA), cannabinol (CBN),cannabinolic acid (CBNA), cannabidivarinic acid (CBDVA),cannabichromenic acid (CBCA), and cannabichromene (CBC).82. The method of any one of embodiments 69-81, wherein the cannabinoidsolution is a Cannabis oil that does not contain any cutting agents.82.1 The method of any one of embodiments 69-82, wherein the cannabinoidsolution is a primary cannabis extract.82.2 The method of embodiment 82.1, wherein the primary cannabis extractis a CO2 extraction or an alcohol extraction of a cannabis plant.82.3 The method of embodiment 82.1, wherein the primary cannabis extractis a CO2 extraction or an alcohol extraction of a cannabinoid-producingmicroorganism culture.83. The method of any one of embodiments 69-82.3, wherein thecannabinoid solution comprises less than 1%, 0.9%, 0.8%, 0.7%, 0.6%,0.5%, 0.4%, 0.3%, 0.2%, or 0.1% exogenous solvents by weight.84. The method of any one of embodiments 69-83, wherein at least 95% ofthe selected cannabinoid is crystallized out of the solution.85. The method any one of embodiments 69-84, wherein at least 50%selected cannabinoid crystallizes out of solution within about 10 hours.86. The method of any one of embodiments 69-85, wherein the crystals ofthe selected cannabinoid comprise crystals that are at least about 25 μmin size.87. The method of any one of embodiments 69-86, wherein the cannabinoidsolution is forced through the filter via centrifugation.88. The method of any one of embodiments 69-87, wherein the nucleationfactor is vacuum.89. The method of embodiment 88, wherein the vacuum is greater thanabout −5 inHg, about −10 inHg, about −15 inHg, about −20 inHg, or about−25 inHg.90. The method of any one of embodiments 69-89, wherein the selectedcannabinoid is at least about 75%, at least about 80%, at least about85%, at least about 90%, at least about 95%, or about 100% dissolved inthe solution at the time step (a) is conducted.90.1 The method of any one of embodiments 69-90, wherein the selectedcannabinoid is selectively crystallized from the cannabinoid solution.91. A method of crystallizing a selected cannabinoid from a cannabinoidsolution, comprising:

(a) providing a cannabinoid solution containing a substantiallydissolved selected cannabinoid, wherein the selected cannabinoid ispresent in the solution at a concentration greater than or equal to itssupersaturation point, and wherein the selected cannabinoid is thehighest concentration cannabinoid in the solution;

(b) exposing the cannabinoid solution of step (a) to nucleation factorscomprising a vacuum and mechanical agitation for a time periodsufficient to crystallize the selected cannabinoid.

91.1 The method of embodiment 91, wherein the solution containing asubstantially dissolved cannabinoid contains microbubbles or dissolvedair that causes bubbling of the solution when exposed to vacuum.91.2 The method of embodiment 91 or 91.1, wherein said solution issubstantially free of any exogenous solvent.92. The method of embodiment 91, 91.1, or 91.2, wherein thesupersaturation point is greater than or equal to 19%, or 30%, by weightof the solution.93. The method of embodiment 91, 91.1, or 91.2 wherein thesupersaturation point is greater than or equal to 24% by weight of thesolution.93.1 The method of any one of embodiments 91-93, wherein the cannabinoidsolution is a primary cannabis extract.93.2 The method of embodiment 93.1, wherein the primary cannabis extractis a CO2 extraction or an alcohol extraction of a cannabis plant.93.3 The method of embodiment 93.1, wherein the primary cannabis extractis a CO2 extraction or an alcohol extraction of a cannabinoid-producingmicroorganism culture.94. The method of any one of embodiments 91-93.3, wherein the vacuum isgreater than about −5 inHg, −10 inHg, −15 inHg, −20 inHg, or −25 inHg.95. The method of any one of embodiments 91-94, wherein the selectedcannabinoid is selectively crystallized from the cannabinoid solution.96. A method of purifying a selected cannabinoid from a solutioncontaining a selected cannabinoid, comprising:

(a) selectively crystallizing the selected cannabinoid from the solutionby:

-   -   (i) providing a cannabinoid solution containing a substantially        dissolved selected cannabinoid, wherein the selected cannabinoid        is present in the solution at a concentration greater than or        equal to its supersaturation point, and wherein the selected        cannabinoid is the highest concentration cannabinoid in the        solution;    -   (ii) exposing the cannabinoid solution of step (a)(i) to a        nucleation factor for a time period sufficient to crystallize        the selected cannabinoid for a time period sufficient to        crystallize the selected cannabinoid, wherein the nucleation        factor is vacuum and mechanical agitation, thereby producing        cannabinoid crystals; and

(b) separating the selected cannabinoid crystals from the cannabinoidsolution of step (a)(ii).

96.1 The method of embodiment 96, wherein the solution containing asubstantially dissolved cannabinoid contains microbubbles or dissolvedair that causes bubbling of the solution when exposed to vacuum.96.2 The method of embodiment 96 or 96.1, wherein said solution issubstantially free of any exogenous solvent.97. The method of embodiment 96, 96.1, or 96.2, wherein thesupersaturation point is greater than or equal to 19%, or 30%, by weightof the solution.98. The method of embodiment 96, 96.1, or 96.2, wherein thesupersaturation point is greater than or equal to 24% by weight of thesolution.98.1 The method of any one of embodiments 96-98, wherein the cannabinoidsolution is a primary cannabis extract.98.2 The method of embodiment 98.1, wherein the primary cannabis extractis a CO2 extraction or an alcohol extraction of a cannabis plant.98.3 The method of embodiment 98.1, wherein the primary cannabis extractis a CO2 extraction or an alcohol extraction of a cannabinoid-producingmicroorganism culture.99. The method of any one of embodiments 96-98.3, wherein the selectedcannabinoid is selectively crystallized from the cannabinoid solution.100. The method of any one of embodiments 96-99, comprising separatingthe cannabinoid from the solution by:

(i) forcing the solution through a filter; and

(ii) collecting the crystallized cannabinoid from the filter, therebyseparating the selected cannabinoid from the cannabinoid solution.

What is claimed is:
 1. A method of crystallizing a selected cannabinoidfrom a cannabinoid solution, comprising: (a) providing a cannabinoidsolution containing a substantially dissolved selected cannabinoid,wherein the selected cannabinoid is the highest concentrationcannabinoid in the solution; (b) exposing the cannabinoid solution ofstep (a) to nucleation factors comprising mechanical agitation and avacuum for a time period sufficient to crystallize the selectedcannabinoid.
 2. The method of claim 1, wherein the solution of (a) isproduced by increasing the temperature of a cannabinoid solution untilthe selected cannabinoid is substantially dissolved in the solution. 3.The method of claim 2, wherein the temperature is increased to betweenabout 50° C. and about 79° C.
 4. The method of claim 1, wherein thecannabinoid solution is substantially free of any alcohol.
 5. The methodof claim 1, wherein the cannabinoid solution comprises less than 15%alcohol by weight of the solution.
 6. The method of claim 1, wherein thecannabinoid solution is substantially free of any exogenous solvent. 7.The method of claim 1, wherein the cannabinoid solution comprises lessthan 15% exogenous solvent by weight of the solution.
 8. The method ofclaim 1, comprising exposing the dissolved cannabinoid solution to anadditional nucleation factor, wherein the nucleation factor is selectedfrom the group consisting of: cold shock, introducing a crystal of theselected cannabinoid into the dissolved cannabinoid solution, aeratingthe solution, and combinations thereof.
 9. The method of claim 1,comprising mechanically agitating the dissolved cannabinoid solutionbefore exposing the cannabinoid solution to the vacuum.
 10. The methodof claim 1, comprising mechanically agitating the dissolved cannabinoidsolution while the cannabinoid solution is exposed to the vacuum
 11. Themethod of claim 1, wherein the selected cannabinoid is selected from thegroup consisting of cannabidiol (CBD), tetrahydrocannabinol (THC),tetrahydrocannabivarin (THCV), cannabidiolic acid (CBDA), cannabidivarin(CBDV), tetrahydrocannabinolic acid (THCA), cannabigerol (CBG),cannabinol (CBN), cannabinolic acid (CBNA), cannabidivarinic acid(CBDVA), cannabigerolic acid (CBGA), cannabichromenic acid (CBCA), andcannabichromene (CBC).
 12. The method of claim 1, wherein the selectedcannabinoid is CBD.
 13. The method of claim 1, wherein the vacuum isstronger than about −5 inHg.
 14. A method of purifying a selectedcannabinoid from a solution of cannabinoids, said method comprising: (a)crystallizing the selected cannabinoid from the solution by: (i)providing a cannabinoid solution containing a substantially dissolvedselected cannabinoid, wherein the selected cannabinoid is the highestconcentration cannabinoid in the solution; (ii) exposing the cannabinoidsolution of step (a)(i) to a nucleation factor for a time periodsufficient to crystallize the selected cannabinoid, wherein thenucleation factor is mechanical agitation and vacuum, thereby producingcannabinoid crystals; and (b) separating the selected cannabinoidcrystals from the cannabinoid solution of step (a)(ii).
 15. The methodof claim 14, wherein the cannabinoid solution is substantially free ofany alcohol.
 16. The method of claim 14, wherein the cannabinoidsolution comprises less than 15% alcohol by weight of the solution. 17.The method of claim 14, wherein the cannabinoid solution issubstantially free of any exogenous solvent.
 18. The method of claim 14,wherein the cannabinoid solution comprises less than 15% exogenoussolvent by weight of the solution.
 19. The method of claim 14, whereinstep (b) comprises: (i) forcing the cannabinoid solution and cannabinoidcrystals through a filter; wherein this step is performed at atemperature below the melting point of the cannabinoid crystals; and(ii) collecting the cannabinoid crystals from the filter, therebyseparating the selected cannabinoid from the cannabinoid solution. 20.The method of claim 19, comprising forcing the cannabinoid solution andcannabinoid crystals through the filter via centrifugation, applicationof pressure, or application of a vacuum.
 21. The method of claim 19,comprising forcing the cannabinoid solution and cannabinoid crystalsthrough the filter via centrifugation.
 22. The method of claim 14,wherein the solution of (a) is produced by increasing the temperature ofthe cannabinoid solution until the selected cannabinoid is substantiallydissolved in the solution.
 23. The method of claim 22, wherein thetemperature is increased to between about 50° C. and about 79° C. 24.The method of claim 14, comprising exposing the dissolved cannabinoidsolution to an additional nucleation factor, wherein the nucleationfactor is selected from the group consisting of: cold shock, introducinga crystal of the selected cannabinoid into the dissolved cannabinoidsolution, aerating the solution, and combinations thereof.
 25. Themethod of claim 14, comprising mechanically agitating the dissolvedcannabinoid solution before exposing the cannabinoid solution to thevacuum.
 26. The method of claim 14, comprising mechanically agitatingthe dissolved cannabinoid solution while the cannabinoid solution isexposed to the vacuum, or a combination thereof.
 27. The method of claim14, wherein the selected cannabinoid is selected from the groupconsisting of cannabidiol (CBD), tetrahydrocannabinol (THC),tetrahydrocannabivarin (THCV), cannabidiolic acid (CBDA), cannabidivarin(CBDV), tetrahydrocannabinolic acid (THCA), cannabigerol (CBG),cannabinol (CBN), cannabinolic acid (CBNA), cannabidivarinic acid(CBDVA), cannabigerolic acid (CBGA), cannabichromenic acid (CBCA), andcannabichromene (CBC).
 28. The method of claim 14, wherein the selectedcannabinoid is CBD.
 29. The method of claim 14, wherein the vacuum isstronger than about −5 inHg.
 30. A method of purifying a selectedcannabinoid from a cannabinoid solution, said method comprising: (a)crystallizing the selected cannabinoid from the solution by: (i)providing a cannabinoid solution containing a substantially dissolvedselected cannabinoid, wherein the selected cannabinoid is the highestconcentration cannabinoid in the solution; (ii) exposing the cannabinoidsolution of step (a)(i) to a nucleation factor for a time periodsufficient to crystallize the selected cannabinoid, wherein thenucleation factor is mechanical agitation and vacuum, thereby producingcannabinoid crystals; and (b) separating the selected cannabinoidcrystals from the cannabinoid solution of step (a)(ii) by: (i) forcingthe cannabinoid solution through a filter; wherein this step isperformed at a temperature below the melting point of the cannabinoidcrystals; and (ii) collecting the cannabinoid crystals from the filter,thereby separating the selected cannabinoid from the cannabinoidsolution.